Lung Disease - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

LUNG DISEASE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Lung Disease: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84018-0 1. Lung Disease-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on lung disease. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON LUNG DISEASE .......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Lung Disease................................................................................. 8 E-Journals: PubMed Central ....................................................................................................... 66 The National Library of Medicine: PubMed ................................................................................ 67 CHAPTER 2. NUTRITION AND LUNG DISEASE .............................................................................. 113 Overview.................................................................................................................................... 113 Finding Nutrition Studies on Lung Disease.............................................................................. 113 Federal Resources on Nutrition ................................................................................................. 115 Additional Web Resources ......................................................................................................... 115 CHAPTER 3. DISSERTATIONS ON LUNG DISEASE .......................................................................... 117 Overview.................................................................................................................................... 117 Dissertations on Lung Disease .................................................................................................. 117 Keeping Current ........................................................................................................................ 118 CHAPTER 4. CLINICAL TRIALS AND LUNG DISEASE .................................................................... 119 Overview.................................................................................................................................... 119 Recent Trials on Lung Disease .................................................................................................. 119 Keeping Current on Clinical Trials ........................................................................................... 134 CHAPTER 5. PATENTS ON LUNG DISEASE..................................................................................... 137 Overview.................................................................................................................................... 137 Patents on Lung Disease............................................................................................................ 137 Patent Applications on Lung Disease ........................................................................................ 150 Keeping Current ........................................................................................................................ 164 CHAPTER 6. BOOKS ON LUNG DISEASE ........................................................................................ 167 Overview.................................................................................................................................... 167 Book Summaries: Federal Agencies............................................................................................ 167 Book Summaries: Online Booksellers......................................................................................... 168 The National Library of Medicine Book Index ........................................................................... 173 Chapters on Lung Disease ......................................................................................................... 175 CHAPTER 7. MULTIMEDIA ON LUNG DISEASE ............................................................................. 179 Overview.................................................................................................................................... 179 Bibliography: Multimedia on Lung Disease .............................................................................. 179 CHAPTER 8. PERIODICALS AND NEWS ON LUNG DISEASE .......................................................... 183 Overview.................................................................................................................................... 183 News Services and Press Releases.............................................................................................. 183 Newsletter Articles .................................................................................................................... 186 Academic Periodicals covering Lung Disease ............................................................................ 188 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 189 Overview.................................................................................................................................... 189 U.S. Pharmacopeia..................................................................................................................... 189 Commercial Databases ............................................................................................................... 190 Researching Orphan Drugs ....................................................................................................... 191 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 195 Overview.................................................................................................................................... 195 NIH Guidelines.......................................................................................................................... 195 NIH Databases........................................................................................................................... 197 Other Commercial Databases..................................................................................................... 200 APPENDIX B. PATIENT RESOURCES ............................................................................................... 201 Overview.................................................................................................................................... 201

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Patient Guideline Sources.......................................................................................................... 201 Finding Associations.................................................................................................................. 212 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 215 Overview.................................................................................................................................... 215 Preparation................................................................................................................................. 215 Finding a Local Medical Library................................................................................................ 215 Medical Libraries in the U.S. and Canada ................................................................................. 215 ONLINE GLOSSARIES................................................................................................................ 221 Online Dictionary Directories ................................................................................................... 222 LUNG DISEASE DICTIONARY................................................................................................. 223 INDEX .............................................................................................................................................. 305

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with lung disease is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about lung disease, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to lung disease, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on lung disease. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to lung disease, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on lung disease. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON LUNG DISEASE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on lung disease.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and lung disease, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “lung disease” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Potential Associations Between Chronic Respiratory Disease and Periodontal Disease: Analysis of National Health and Nutrition Examination Survey III Source: Journal of Periodontology. 72(1): 50-56. January 2001. Contact: Available from American Academy of Periodontology. 737 North Michigan Avenue, Suite 800, Chicago, IL 60611-2690. (312) 573-3220. Fax (312) 573-3225. Summary: Associations between poor oral health and chronic lung disease have recently been reported. This article reports on a study that evaluated these potential associations by analyzing data from the National Health and Nutrition Examination Survey III (NHANES III), which documents the general health and nutritional status of randomly selected United States subjects from 1988 to 1994. This cross sectional, retrospective study of the NHANES III database included a study population of 13,792

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subjects older than 20 years of age, with at least 6 natural teeth. A history of bronchitis or emphysema was recorded from the medical questionnaire, and a dichotomized variable combined those with either chronic bronchitis or emphysema, together considered as chronic obstructive pulmonary disease (COPD). Subject lung function and oral health status were assessed. Analyses adjusted for age, gender, race and ethnicity, education, income, frequency of dental visits, diabetes mellitus, smoking, and alcohol use. The mean age of all subjects was 44.4 years (plus or minus 17.8 years); the mean age of subjects with COPD was 51.2 years and subjects without COPD was 43.9 years. Subjects with a history of COPD had more periodontal attachment loss (a measure of periodontal disease) than subjects without COPD. A trend was noted in that lung function appeared to diminish with increasing periodontal attachment loss. The authors conclude that these findings support recently published reports that suggest an association between periodontal disease and COPD. 4 tables. 46 references. •

Ischemic Hepatitis: Clinical and Laboratory Observations of 34 Patients Source: Journal of Clinical Gastroenterology. 26(3): 183-186. April 1998. Contact: Available from Lippincott-Raven Publishers. P.O. Box 1550, Hagerstown, MD 21741. (800) 638-3030 or (301) 714-2300. Summary: Ischemic hepatitis, a relatively infrequent disorder occurring in 0.16 percent to 0.50 percent of patients admitted to medical intensive care units, often follows episodes of hypotension or acute heart failure. This article reports on a retrospective analysis of 34 patients undertaken to examine the possible contribution of the various baseline characteristics of patients with ischemic hepatitis to the severity of the hepatic (liver) damage. In all patients, liver disease was unexpected, and in some, liver dysfunction dominated the clinical picture. All patients had high serum glutamic pyruvic transaminase (SGPT) and lactic dehydrogenase levels. Most patients had coagulopathy with a prolonged prothrombin time. The most common diagnosis on admission was respiratory distress secondary to various causes. Before the development of hepatic dysfunction, respiratory failure and hypoxemia (low blood levels of oxygen) were observed in 68 percent of the patients, whereas hypotension (low blood pressure) was observed in only 38 percent. More than 90 percent of the patients had three or more associated comorbid conditions. The most frequent of these were left heart failure (88.2 percent), right heart failure (67.6 percent), chronic obstructive lung disease (58.8 percent), and chronic renal failure (55.9 percent). During the acute episode, more than 90 percent of the patients had transient deterioration of their renal function. Hypoglycemia was noted in 11 patients (32.4 percent) and the glucose level was inversely correlated with the SGPT level. Fourteen patients (41.2 percent) died during the 3 month followup period, but none from hepatic injury. None of the clinical or laboratory parameters that were measured predicted mortality. Clearly, ischemic hepatitis is associated with a high risk of death. Characteristic patients are those with multiple underlying systemic diseases and conditions, especially those with left heart failure. The authors stress that results of liver function tests and levels of liver enzymes should be monitored in these patients, particularly when they are admitted for respiratory deterioration and episodes of hypotension. 2 tables. 22 references. (AA).

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Seven-Year Survival Rate After 85 Years: Relation to Alzheimer Disease and Vascular Dementia Source: Archives of Neurology. 55: 1226-1232. September 1998.

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Summary: This article describes an investigation of the relationship between very elderly individuals' survival rate and Alzheimer's disease (AD), vascular dementia, and other mental and physical disorders. Data showed that the 7-year survival rate after age 85 was 34.5 percent higher in women than in men, and that AD and vascular dementia predicted 30.7 percent of deaths in men and 49.7 percent of deaths in women. A regression analysis showed that mortality in men was predicted by the presence of chronic obstructive lung disease, AD, vascular dementia, cancer of the gastrointestinal tract, and skin cancer; in women by vascular dementia, AD, cerebrovascular disorders, congestive heart failure, hypertension, myocardial infarction, and cancer of the gastrointestinal tract. Life expectancy decreased with severity of dementia; survival time in individuals with mild AD did not differ from that in individuals with no dementia. The authors conclude that AD and vascular dementia influence the mortality rate considerably in extreme old age. 2 figures, 3 tables, 52 references. (AA-M). •

Differential Diagnosis of Dementia, Delirium and Depression: Implications for Drug Therapy Source: Drugs and Aging. 5(6): 431-445. December 1994. Summary: This article discusses the differential diagnosis, evaluation, and treatment options for dementia, delirium, and depression. It presents the clinical features and causes of each disorder and the neuropsychological and laboratory tests used in diagnosis. Comprehensive clinical evaluation is necessary because these disorders are not mutually exclusive. Furthermore, physical diagnoses, such as chronic obstructive lung disease, congestive heart failure, stroke, and endocrine disorders are frequently associated with depressive symptoms. Laboratory testing is required to exclude concurrent metabolic, endocrine and infectious disorders, and drug effects. Imaging studies should be obtained selectively in patients with signs and symptoms, such as focal neurological findings and gait disturbances, which are suggestive of structural lesions: stroke, subdural hematoma, normal pressure hydrocephalus, and brain tumors. Appropriate management involving pharmacological and nonpharmacological measures could result in significant improvement in most patients with these syndromes. In delirious patients the underlying illness may be treated concomitantly with the use of psychotropics, if necessary. Although no current medications have been shown to have a significant effect on the functional status of patients with the two most common causes of dementia, Alzheimer's disease (AD) and multi-infarct dementia, the management of concomitant illness in these patients may result in improved function for as long as a year. Tacrine (Cognex) improves cognitive function slightly in selected patients with AD over short periods. Finally, the treatment of depression with medications or electroconvulsive therapy may result in significant reductions in mortality and morbidity. 4 tables, 43 references. (AA-M).

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Pedometer-determined Ambulatory Activity in Individuals with Type 2 Diabetes Source: Diabetes Research and Clinical Practice. 55(3): 191-199. 2002. Summary: This article reports on a cross sectional study on pedometer-determined ambulatory activity, defined as steps per day, in 160 individuals (98 males, 62 females; mean age 52.4 years plus or minus 5.3 years, body mass index 32.3 plus or minus 5.7) with type 2 diabetes. Participants took 6,662 steps (plus or minus 3,077) per day, less than that reported in samples with diabetes and more than that reported for samples living with more restrictive chronic conditions including claudication, joint replacement, chronic obstructive lung disease (COLD), and chronic heart failure. Steps per day and BMI were inversely and significantly correlated. Further, there was a significant

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difference between BMI categories (from normal weight to obesity class III) with regard to steps per day. The authors note that objective quantification of ambulatory activity via simple and inexpensive pedometers permits researchers and practitioners to easily screen for level of activity along a continuum. 1 figure. 5 tables. 33 references. •

Epidemiology of Surgically Managed Pelvic Organ Prolapse and Urinary Incontinence Source: Obstetrics and Gynecology. 89(4): 501-506. April 1997. Summary: This article reports on a study to determine the incidence of surgically managed pelvic organ prolapse and urinary incontinence (UI) in a population-based cohort, and to describe their clinical characteristics. The retrospective cohort included all patients undergoing surgical treatment for prolapse and incontinence during 1995; all were members of Kaiser Permanente Northwest, which included 149,554 women aged 20 or older. A standardized data collection form was used to review all inpatient and outpatient charts of the 395 women identified. Variables examined included age, ethnicity, height, weight, vaginal parity, smoking history, medical history, and surgical history, including the preoperative evaluation, procedure performed, and details of all prior procedures. Results showed that the age-specific incidence increased with advancing age. The lifetime risk of undergoing a single operation for prolapse or incontinence by age 80 was 11.1 percent. Most patients were older, postmenopausal, parous, and overweight. Nearly half were current or former smokers, and one-fifth had chronic lung disease. Reoperation was common (29.2 percent of cases), and the time intervals between repeat procedures decreased with each successive repair. The authors call for further epidemiologic research in order to determine the etiology, natural history, and longterm treatment outcomes of these conditions. 1 figure. 8 tables. 21 references. (AA-M).

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Major Complications of Coeliac Disease Source: Clinical Gastroenterology: International Practice and Research. 9(2): 351-369. June 1995. Contact: Available from W.B. Saunders Company. Order Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 545-2522. Fax (800) 874-6418 or (407) 352-3445. Summary: This article reviews the major complications of celiac disease. The author notes that it is claimed that adherence to a gluten-free diet returns patients with celiac disease to a normal life expectancy and that they ultimately die from unrelated causes. While this may be true for an individual patient, the mortality rate for all patients with celiac disease is increased above that of the general population. This increased mortality rate is largely from an increased prevalence of malignant disease, particularly malignant lymphoma. The author hypothesizes that this may be partly because a large number of patients have subclinical or silent celiac disease and thus would not realize that they ought to be following a gluten-free diet. The author details the various complications, included malignant lymphoma, other malignancies, chronic ulcerative enteritis, liver disease, lung disease, neurological disorders, and hyposplenism. The author reports on research findings that suggest that enteropathy associated T-cell lymphoma arises in the setting of celiac disease and evolves from reactive intraepithelial lymphocytes through a low-grade lymphocytic neoplasm to a high-grade tumor, which is usually the cause of the presenting symptoms. Most cases of chronic ulcerative enteropathy (ulcerative jejunitis) are probably part of the same disease process. Carcinoma of the pharynx and esophagus, and adenocarcinoma of the small intestine, are increased in frequency in

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patients with celiac disease. The increased risk of carcinoma of the esophagus may be related to vitamin A deficiency. Splenic atrophy occurs frequently in patients with celiac disease and is related to the severity of the disease and degree of dietary control. 7 figures. 75 references. •

Suspected Kidney Disease: Putting Urinalysis Clues Into Context, Part 1 Source: Consultant. 41(13): 1749-1750, 1752-1753, 1756-1757. November, 2001. Contact: Available from Cliggott Publishing Company. 330 Boston Post Road, Darien, CT 06820-4027. (203) 661-0600. Summary: This first article in a two part series uses a case based approach to illustrate typical urinalysis results found in common renal diseases. The authors show how these results can be integrated with findings from the history, physical examination, and other laboratory studies to arrive at a reliable diagnosis and to guide treatment. Typical urinalysis (urine testing) results in patients with nephritic disease are proteinuria greater than 2 to 3 grams per 24 hours, blood detected by dipstick and microscopic examination, and red blood cell (RBC) casts in the urine. Other findings may include cryoglobulinemia (both polyclonal and monoclonal), low complement levels, and gross hematuria. Characteristic urine findings in patients with nephrotic disease are proteinuria greater than 4 grams per 24 hours, no blood or less than is seen in nephritic disease, and casts without RBCs. Nephrotic disease is also associated with edema, a low albumin level, and a high cholesterol level. An antineutrophilic cystoplasmic antibody (ANCA) assay is useful in determining the underlying cause of rapidly progressive glomerulonephritis. For example, in a patient with azotemia and cavitary lung disease, the presence of cytoplasmic ANCA suggests Wegener granulomatosis. 3 figures. 4 tables. 10 references.

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Methotrexate Pulmonary Toxicity Source: Rheumatic Disease Clinics of North America. 23(4):917-937; November 1997. Summary: This journal article for health professionals focuses on methotrexate (MTX) pulmonary toxicity, which is a well-recognized complication of MTX treatment of rheumatic disease. The article reviews the different types of MTX-induced pulmonary diseases, including acute interstitial pneumonitis, interstitial fibrosis, noncardiogenic pulmonary edema, pleuritis and pleural effusions, and pulmonary nodules. It describes the clinical features of MTX-induced pulmonary disease, including its symptoms; physical signs; and laboratory, radiographic, and pathologic findings. The article reports on the proposed criteria for diagnosing MTX-induced lung disease. It identifies the risk factors for MTX-induced lung disease, including MTX dose, duration, and treatment schedules; demographic factors; clinical laboratory parameters; and pre-existing lung disease. In addition, the article suggests an approach for managing MTX-induced pulmonary disease and the rheumatic disease patient who develops new pulmonary symptoms while receiving MTX. It stresses the need for educating all patients receiving MTX about its potential life-threatening drug toxicity. 67 references, 3 figures, and 3 tables. (AA-M).

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Extramuscular Manifestations in Idiopathic Inflammatory Myopathies Source: Current Opinion in Rheumatology. 10(6): 556-561. November 1998. Summary: This journal article provides health professionals with information on the extramuscular manifestations of the major syndromes of chronic idiopathic

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inflammatory myopathy, including cutaneous, pulmonary, and cardiac manifestations; calcinosis; and joint involvement. Dermatological manifestations in dermatomyositis are often so characteristic that they are virtually pathognomonic. Histopathological findings that are typical of dermatomyositis include focal epidermal atrophy, liquefaction of the basal layer, mucin deposition, and a perivascular and dermal infiltration of mononuclear cells and lymphocytes. Therapy for dermatological manifestations of dermatomyositis depends on whether the patient has both skin and muscle involvement or the characteristic rash in the absence of overt muscle disease. In the former case, systemic treatment with agents such as corticosteroids, intravenous gamma globulin, methotrexate, azathioprine, cyclosporine, and hydroxychloroquine is the usual standard of care. In the latter case, treatment appropriate for the severity of disease manifestations would seem the best approach. Calcinosis is frequently seen in children or young adults with dermatomyositis. Therapeutic agents include warfarin, colchicine, bisphosphonates, intralesional corticosteroids, phosphate binding antacids, probenecid, and calcium channel blocking agents. Respiratory complaints can be a prominent and serious feature in people who have inflammatory muscle disease. Pulmonary problems include exertional dyspnea, upper pharyngeal weakness and dysfunction, infections, interstitial lung disease, and aggressive diffuse lung disease. Corticosteroids, immunosuppressives, methotrexate, and intravenous gamma globulin have been used to treat interstitial lung disease. Although clinically symptomatic cardiac involvement in polymyositis and dermatomyositis is uncommon, various abnormalities of structure and function have been described. Joint involvement can occur in both polymyositis and dermatomyositis. This manifestation is characterized by arthralgia or arthritis of the wrists, knees, and small joints of the hands. Although gastrointestinal involvement in dermatomyositis and polymyositis is not usually clinically apparent, dysphagia that can be complicated by aspiration does occur. Abnormalities of gastric emptying have also been documented. 1 table and 52 references. (AA-M). •

What's New in Pathology, Pathophysiology and Conservative Treatment of Benign Esophageal Disorders? Source: Diseases of the Esophagus. 10(2): 149-154. April 1997. Contact: Available from Pearson Professional Ltd. P.O. Box 77, Harlow, Essex CM19 5BQ, England. Phone: 44 0 1279 623 924; Fax: 44 0 1279 639 609. Summary: This review article considers advances in the pathology, pathophysiology, and conservative treatment of benign esophageal disorders. Topics include the investigation of esophageal motility; motility and esophageal disease; gastroesophageal reflux disease (GERD), including its pathophysiology, symptoms, investigation, histology, endoscopy, and medical treatment; Barrett's esophagus; GERD and lung disease; esophageal strictures, foreign bodies, and cancer; esophageal complications of disease, injury or treatment; achalasia; and esophageal varices. The authors summarize recent research in each of these topic areas. Treatment options for GERD include weight reduction and drug therapy (omeprazole, ranitidine, lansoprazole). The authors discuss the esophageal complications of AIDS, notably candidal esophagitis. The mainstay of treatment for achalasia is pneumatic dilatation. 75 references. (AA-M).

Federally Funded Research on Lung Disease The U.S. Government supports a variety of research studies relating to lung disease. These studies are tracked by the Office of Extramural Research at the National Institutes of

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Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to lung disease. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore lung disease. The following is typical of the type of information found when searching the CRISP database for lung disease: •

Project Title: A PROTEOMICS APPROACH IN THE STUDY OF NOVEL COPD MARKERS Principal Investigator & Institution: Djukanovic, Ratko; University of Southampton Highfield Southampton, Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): COPD is a major health problem worldwide, but our level of understanding of its mechanisms, when compared to the other important airway disease, asthma, is relatively poor. COPD is a disease which progresses at a slow rate, which makes it very difficult to study its natural history and the impact of any therapeutic intervention. For all these reasons, it is vitally important to discover biomarkers that are elective for COPD, i.e., they are not general markers of lung inflammation and remodeling, and are prognostic for the rate of clinical deterioration. A number of non-invasive markers have been studied to date; to our knowledge, none of these have fulfilled the above criteria. As with other inflammatory lung diseases, a host of inflammatory and remodeling processes are involved in the pathogenesis of COPD, which render a singlemarker approach unlikely to succeed. We hypothesize that a number of proteins or protein isoforms are differentially expressed in the airway lining fluid in COPD and that these reflect the chronic pathology of COPD, rather than the chronic and acute effects of smoking. We propose to test this hypothesis using a proteomics approach as our primary, unbiased filter, to identify a set of 15 differentially expressed proteins (DEPs) that are present in a group of meticulously characterized subjects with COPD, but not present in those who have no evidence of lung damage despite an equivalent smoking history. Our programme is staged in a way to optimize the use of the state-of-the-art proteomics technology and precious archival samples collected over up to 17 years at the University of Nebraska and more recently in Southampton. Because we believe that patterns (groups) of biomarkers are more strongly related to COPD, we will apply multivariate analyses to identify the DEPs, which will thus become Early Candidate COPD-Selective Biomarkers. We will then develop antibodies against these in order to provide reagents for immunoassays. The latter will be applied to potentially as many as 480 subjects who have COPD, chronic severe asthma, or are healthy smokers or non-smokers. This will allow us to follow a logical sequence of further selection of biomarkers with respect to their selectivity for COPD, presence in early stages of smoke-induced lung damage and their prognostic

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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value in terms of clinical deterioration and decline in lung function. Finally, applying the antibodies to archival lung tissue samples we will be able to localize the COPDselective proteins to the airway and alveoli, adding valuable knowledge to our understanding of COPD mechanisms. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ACADEMIC TRAINING PROGRAM IN PEDIATRIC PULMONARY DISEASE Principal Investigator & Institution: Abman, Steven H.; Professor, Pulmonary Medicine; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 15-JUL-1994; Project End 30-JUN-2004 Summary: Advances in our understanding and treatment of childhood respiratory disorders have been limited by a lack of insight into basic mechanisms of disease and the development of novel therapeutic strategies. The purpose of this program is to provide rigorous multi-disciplinary training for academically-oriented pediatricians interested in childhood lung diseases. This proposal is a renewal of the NIH Training Program in Pediatric Lung Disease at the University of Colorado School of Medicine, and represents the continuation of a well-established program that has existed since 1988. This current proposal has been expanded to represent the evolution of our training program and to reflect our highly interactive, multi-disciplinary faculty. Strengths of this program include benefits derived from the integration of extensive resources of two collaborating hospitals (The Children's Hospital (TCH) and National Jewish Medical and Research Center (NJMRC)) and five research units at the NJMRC and the UCHSC campus (Developmental Lung Biology Laboratory, Pediatric Heart Lung Center Laboratory, the Perinatal Research Facility, and the Cardiovascular Pulmonary Laboratories). These resources are combined into a versatile training environment for both basic and applied research. Faculty in this program include the PIs of 2 PPGs, 2 SCORs, a Therapeutic Development Center Award in Cystic Fibrosis, an NIH Clinical Research Center Grant, and several individual awards that address basic, applied and clinical research questions in the area of pulmonary biology. Collaborations between laboratory and clinical investigators are a major strength of this proposal, enhancing interactions between scientists and clinicians from diverse backgrounds and encouraging "bench to bedside" approaches to pediatric lung disease. All participants in the training program are full-time academic faculty, and include pediatric pulmonary and critical care physician- investigators, along with several basic (PhD) and other scientists from throughout UCHSC. The most promising individuals with clearly defined academical goals are selected from candidates within our pediatric pulmonary, critical care and neonatology fellowship training programs. After a clinical year of training (funded from other sources), laboratory or clinical research experience is provided under the direct mentorship of a senior investigator. Structured course work in statistics, molecular biology, cell physiology, ethics, and other areas are provided to the trainees. Review of fellows' progress is closely monitored by the head of the training grant, fellowship directors, their laboratory mentor and special advisors to the program. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ADENOSINE SIGNALING AND LUNG FIBROSIS Principal Investigator & Institution: Blackburn, Michael R.; Assistant Professor; Biochem and Molecular Biology; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225

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Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 30-JUN-2006 Summary: (provided by applicant): Interstitial lung disease leads to more than 30,000 hospitalizations and 5,000 deaths yearly in the United States. A subset of interstitial lung disease known as idiopathic pulmonary fibrosis (IPF) is particularly devastating. Basic research into the mechanisms that govern this disease are needed to help develop novel therapies for its treatment. The focus of this proposal is to characterize a novel model of lung fibrosis that implicates adenosine signaling in this disease. Adenosine is a signaling nucleoside that engages specific adenosine receptors on the surface of target cells to elicit a vast array of cellular responses. Elevated adenosine levels are thought to play a role in inflammatory lung diseases such as asthma and COPD; however, the involvement of this signaling pathway in IPF has not been examined. We have recently generated a line of mice that contain low levels of the enzyme adenosine deaminase (ADA), which is responsible for controlling the levels of adenosine in tissues and cells. These partially ADA-deficient mice exhibit progressive elevations in lung adenosine concentrations and in turn die from severe interstitial lung disease characterized by the histologic, immunologic and inflammatory hallmarks of IPF. This suggests that chronic elevations in adenosine may access signaling pathways that lead to the inflammation and damage seen IPF. Therefore, the hypothesis being tested is that chronic elevations in adenosine contribute to lung inflammation and fibrosis. Four specific aims are designed to address this hypothesis: Aim 1, Characterize the lung fibrosis seen in partially ADAdeficient mice and determine the dependence of this phenotype on elevations in adenosine. Aim 2, Characterize the pattern of adenosine receptor expression in the lungs of partially ADA-deficient mice and determine their function using genetic and pharmacologic approaches. Aim 3, Examine adenosine-signaling pathways in an established model of lung fibrosis. and Aim 4, Examine the efficacy of novel therapies on lung fibrosis. Knowledge obtained from these experiments will improve our understanding of the cellular signaling pathways involved in interstitial lung diseases such IPF, which will aid the development of adenosine-based therapeutics for the treatment of this deadly disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AIRWAY EPITHELIAL CELL CHLORIDE CHANNELS Principal Investigator & Institution: Wine, Jeffrey J.; Psychology; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2001; Project Start 30-SEP-1996; Project End 30-JUN-2001 Summary: (Taken directly from the application) The central hypothesis of our research is that the loss of CFTR-mediated, apical membrane chloride conductance is the fundamental physiological defect that leads to airways disease in cystic fibrosis. The general goal of our research is to confirm or negate that hypothesis. The most puzzling aspect of CF lung disease is how it begins. A direct attack on that question is not possible at present because no adequate animal model of human CF lung disease exists. Elsewhere, we propose a strategy to produce such a model. Here, we propose experiments that are feasible with available model tissues and that deal with two of most basic questions in CF research: how does CFTR operate as an ion channel, and what other chloride ion channels are important players in the lung. The proposal has 4 specific aims. Aim 1 is to understand the mechanism and functional significance of natural "lock-open" kinetics that we have discovered in CFTR channels of human airway cells. Aim 2 is to test the hypothesis that some mutations in CFTR lead to disease in whole or in part because they interfere with CFTR's ability to display locked-open kinetics. Aim 3 is to identify other chloride channels and determine their role in airway

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cell function. Aim 4 is to study changes in channel populations that occur with epithelial cell polarization. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ALTERATION OF PULMONARY IMMUNE SYSTEM BY DIESEL PARTICLE Principal Investigator & Institution: Ma, Joseph K.; Professor; Basic Pharmaceutical Sciences; West Virginia University P. O. Box 6845 Morgantown, Wv 265066845 Timing: Fiscal Year 2001; Project Start 01-APR-2000; Project End 31-MAR-2003 Summary: The objective of the proposed research is to investigate the effects of diesel exhaust particles (DEP) on the development of chronic lung diseases in animal models. Preliminary studies in rates showed that DEP induced pulmonary inflammation and inhibited alveolar macrophage (AM) host defense function. Specifically, DEP inhibited AM secretion of cytokines in response to endotoxin stimulation, and resulted din altered thiol (cysteine and glutathione) levels that are known to regulate T lymphocyte function. These results indicate that DEP can change the susceptibility of the lung to bacterial infection and allergic sensitization. The proposed research will study the mechanism of the DEP effects indicated in the preliminary studies based on the following hypotheses. (1) DEP impair cell-mediated immunity in the lung, which can be illustrated by measuring the weakened host defense against the obligate intercellular pathogen, listeria monocytogens; (2) DEP augment antigen- elicited humoral immune responses, increasing the likelihood and severity of sensitization, and worsening the clinical outcome. Theses hypotheses will be tested using a L. Monocytogens rate model for cellmediated immunity and the Brown-Norway rate (BNR) model for allergic sensitization. Exposure of rates to DEP will be carried out by inhalation. The DEP effects will be assessed with an acute and a sub-chronic exposure protocol, via the following studies: (a) to establish the effects of inhalation DEP exposure on pulmonary inflammation; (b) to characterize the pulmonary immune-inflammatory responses to L. Monocytogens and the effect of DEP on the host defense mechanism; to assess the integrative effect of DEP and antigen sensitization on airway hyper reactivity; and (d) to establish the DEP effects on T lymphocyte function, AM- regulated thiol levels and cytokine productions in the BNR model. In year 1, studies will be focused on the effects of DEP on Listeria infection and allergic sensitization via acute DEP exposure. A sub-chronic exposure protocol will be established. In years 2 and 3, studies will be focused on the interactive effects of the disease state with sub-chronic DEP exposure and the mechanism(s) by which DEP alter pulmonary immunity. By using the two disease models, this research will characterize the cellular (TH1) and humoral (TH2) responses to DEP exposure, and test the hypothesis that DEP suppress the cellular buy enhance humoral immune responses by altering AM-regulated thiol homeostasis in the lung. The strengths of this proposal are 1) the strong and robust assumptions underlying the hypotheses, 2) the extent of preliminary data available, 3) the investigator's experience in these methods and preparations, and 4) the inhalation system, which is proven. The weaknesses of this proposal are 1) its complexity and the complicated logistics required for execution, and 2) uncertainties in extrapolation to human exposure and expression of disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ASBESTOS AND NO2 IN ENVIRONMENTAL LUNG DISEASE Principal Investigator & Institution: Heintz, Nicholas H.; Professor; Pathology; University of Vermont & St Agric College 340 Waterman Building Burlington, Vt 05405

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Timing: Fiscal Year 2001; Project Start 15-AUG-1998; Project End 31-JUL-2002 Summary: Exposure of the human lung to environmental particulates and gases contributes to a variety of diseases, including pulmonary fibrosis and cancer. Previous work in our research group has shown that asbestos, reactive oxygen species (ROS), and reactive nitrogen species (RNS) trigger specific cell signaling pathways in target cells of the lung, leading to activation of transcription factors such as AP-1 and NF-KB. These and other transcription factors are involved in cellular decisions leading to phenotypic changes involved in the initiation of lung disease. To extend our understanding of cellular responses to mixtures of chemical and physical agents, we propose to study the effects of chrysotile asbestos and nitrogen dioxide (NO2), either alone or together, on three endpoints of exposure: cell survival, cell cycle progression, and apoptosis. First, we will characterize the responses of rat lung epithelial (RLE) cells and rat lung fibroblasts (RLF) to asbestos and/or N02, in regard to the activation of the transcription factors AP-1, NF-KB, and E2F and their downstream target genes. Activation of cyclindependent kinases (CDKs), metabolism of their protein inhibitors (i.e., CKIs p15, pl6, pl8, p2l, and p27),and phosphorylation of retinoblastoma family proteins (pRB and pl3O) will be studied as regulators of cell cycle progression. Cell imaging techniques, flow cytometry and activation of proteases will be used to measure apoptotic responses. Transient expression of dominantnegative regulatory molecules will be used to dissect mechanisms of exposure responses. For physiological relevance, results from experiments using models for cell cycle control and apoptosis in Vitro will be verified by inhalation studies using mice. Finally, to test the contributions of specific proteins such as p53, CKIS, and other candidate cell cycle regulators in cell cycle activation and/or apoptosis by asbestos and N02, inhalation studies will be performed in transgenic mice lacking specific genes of interest. Dissection of the role of cell cycle and survival regulators in proliferative and apoptotic responses to the combined effects of asbestos and N02 may lead to new biomarkers for exposure of the human lung to chemical mixtures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ASTHMA CANDIDATE GENES IN ALPHA 1-ANTITRYPSIN DEFICIENCY Principal Investigator & Institution: Demeo, Dawn L.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a disease of tremendous public health concern. Cigarette smoking is the major environmental risk for disease, but the development of airflow obstruction is variable amongst smokers. COPD is likely a genetically complex disease, but alpha 1-antitrypsin (AAT) deficiency is the only known genetic risk factor for COPD. Variability in lung function decline also exists among individuals with severe AAT deficiency (genotype PI ZZ), suggesting the presence of other genetic factors relevant to disease development and progression. A subset of individuals with COPD will also have manifestations of asthma. We hypothesize that genes associated with asthma and asthma-related phenotypes represent modifying factors for the expression of COPD in individuals with severe AAT deficiency. Through the funded NIH project "Genetic Modifiers of Alpha 1Antitrypsin Deficiency" (RO1 HL 68926), 400 families are being collected that include at least two adult PI ZZ siblings. We propose to investigate asthma phenotypes and asthma candidate gene polymorphisms in these families, using a candidate gene approach and family-based association tests for analysis, to pursue three distinct

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hypotheses, 1). We hypothesize that asthma phenotypes are common in PI ZZ AAT deficient individuals, and may be modified by age, sex, and level of lung function. 2) We hypothesize that asthma candidate gene polymorphisms are associated with asthma phenotypes in PI ZZ individuals. 3) We hypothesize that asthma candidate gene polymorphisms are associated with COPD phenotypes in PI ZZ individuals. Familybased association analysis of asthma candidate genes in a population enriched to develop COPD from a major gene effect will be complementary to the ongoing project that uses genome scanning and linkage analysis to identify modifier genes for COPD in this population. Understanding modifying factors for lung disease in individuals with AAT deficiency will potentially have important prognostic and therapeutic impact. The identification of modifying factors of COPD in AAT deficiency may have significant public health relevance to COPD patients without AAT deficiency. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CELLULAR AND MOLECULAR MECHANISMS OF LUNG DISEASE Principal Investigator & Institution: Stanton, Bruce A.; Professor; Physiology; Dartmouth College 11 Rope Ferry Rd. #6210 Hanover, Nh 03755 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008 Summary: (provided by applicant): The goals of this application are to increase the number of investigators in New Hampshire who are competitive in securing NIH funding, and to establish a Lung Biology Center that will be nationally recognized and free standing in five years. Based on a core of existing collaborative and multidisciplinary faculty at Dartmouth and Keene State College (KSC) along with other investigators in the State, COBRE funding will provide resources to develop junior faculty and infrastructure necessary to attain Center status. Faculty growth and development will be facilitated in five ways: 1) recruitment of three tenure-track faculty: two at Dartmouth, and one at Keene State College; 2) mentored development of four junior investigators already at Dartmouth, and one already at Keene State College; 3) linkage between Dartmouth, Keene State College and investigators in the State who provide expertise not available at Dartmouth; and 5) synergistic scientific collaboration through the research projects and associated administrative and proteomic cores. Under the leadership of Dr. Stanton, the current Director of the Lung Biology Program at Dartmouth, together with substantial institutional commitments, we are confident that the existing base of investigators will expand and mature with COBRE funding to an established Center, comprised of faculty who will be more competitive in obtaining NIH funding, and thereby enhance the research grant portfolio of the State. The five research projects exhibit a multidisciplinary approach characteristic of a Center and are connected by the common themes of lung biology and disease including cystic fibrosis (CF), cancer and lung injury as well as proteomics. Project 1 will examine biofilm formation in the CF lung. Project 2 will study ?F508-CFTR trafficking. Project 3 examines the structural basis of the CFTR-PDZ protein interactions that regulate the function and trafficking of CFTR. The ultimate goals of Projects 1-3, which are complementary in approach, are to elucidate the cellular mechanisms of lung disease in CF. In Project 4 the major goal is to identify biomarkers that can be used to determine causal relationships between exposure to airborne pollutants and increased incidence of cancer, obstructive airway disease and asthma. The goal of Project 5 is to use a multilevel approach using Geographic Information Systems and case-reference methods to study the environmental epidemiology of lung cancer. Together these projects will contribute to the growth of our Program and to a better understanding of the cellular and molecular

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mechanisms that underlie lung disease. The long-term goal of our Program is to conduct translational studies to develop new treatments and cures for lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOKINE AND CHEMOKINE RECEPTORS IN IPF Principal Investigator & Institution: Hogaboam, Cory M.; Associate Professor; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 26-DEC-2001; Project End 30-NOV-2006 Summary: (Applicant's Abstract) Interstitial lung disease (Il-D) encompasses a group of pulmonary inflammatory disorders that are characterized by excessive tissue injury and progressive fibrosis. Clinical and laboratory evidence suggest that ILD is a consequence of a poorly regulated pulmonary inflammatory process because of the persistence of one or several inflammatory signals. Recent experimental data suggest that the lung fibroblast is not a bystander during chronic inflammatory responses in the lung, rather this structural cell has a very specialized role in the recruitment and regulation of immune cells that infiltrate the interstitial space. The role of the fibroblast during ILD has expanded because of the recent recognition that this cell markedly increases the generation of chemotactic proteins (chemokines) and directly responds to these factors through the expression of high-specialized chemokine receptors. Chemokines affect both the proliferation and synthetic capacity of pulmonary fibroblasts. Although increased chemokine levels during ILD have been reported, little is known about changes in the chemokine and chemokine receptor expression in the fibroblast during ILD, nor is it known whether the temporal pattern of expression of chemokine receptors by these cells may aid in differentiating the various pathologically distinct types of ILD or success of ILD treatment. Thus, the overall aim of this proposal is to characterize the pattern of chemokine and chemokine receptor expression associated with non-specific interstitial pneumonia (NSIP)-cellular, NSIP-fibrotic, usual interstitial pneumonia (UIP)discordent, and UIP-cordent in open lung biopsies (OLB), fibrotic foci and cultured fibroblasts from OLB and transbronchial biopsies. The following specific aims will be addressed using powerful new techniques including TAQMAN quantitative polymerase chain reaction (PCR) and laser capture microscopy: 1) to characterize the chemokine and chemolcine receptor profile in OLB from patients at the time of ILD diagnosis, and specifically identify the chemokine receptor profile in fibrotic foci from histological samples. 2) to characterize the chemokine and chemokine receptor profile in fibroblasts cultured from open lung biopsies at the time of ILD diagnosis. 3) to examine changes in the chemokine and chemokine receptor profile in cultured transbronchial biopsy fibroblasts at defined intervals after initial ILD diagnosis and during a defined ILD treatment regimen. Taken together, these studies entail an examination of the expression of chemokines and their receptors in OLB, fibrotic foci and cultured lung fibroblasts at the time of diagnosis and during ILD treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHEMOKINE BLOCKADE TO PRESERVE LUNG DEVELOPMENT Principal Investigator & Institution: Auten, Richard L.; Pediatrics; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2007 Summary: Chronic lung disease in prematurity (CLD) may affect as many as 50% of very low birthweight newborns. CLD confers added risk for abnormal

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neurodevelopmental outcome. Inflammation in response to adequate antioxidant defenses in premature newborns is central to the pathophysiology of lung injury leading to CLD. Present therapy includes glucocorticoids which may adversely affect lung, somatic and central nervous system development.,. Targeted immunotherapy blocking early inflammatory-induced lung injury may prevent the development of CLD and avoid adverse steroid effects. Our hypothesis is that blocking leukocyte influx and/of function will prevent chronic lung disease in the hyperoxia-exposed rodent model. The proposed studies will use hyperoxia-exposed newborn rodents to study the mechanisms of inflammatory effects on lung development in response to serve oxidant stress, as a model of CLD. Neutrophil and macrophage influx/function will be modified by using specific anti- chemokine antibodies and chemokine receptor antagonists. The contribution of key neutrophil functions will e studied in gene knockout mice lacking these functions. Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during initiation of hyperoxia-induced lung injury. Aim 1 will determine which aspect of neutrophil and/or macrophage influx/function contributes most to biochemical oxidant stress in newborn lung during initiation of hyperoxia-induced lung injury. Aim 2 will determine the specific contributions of leukocyte influx/function to DNA damage, growth arrest, and pathologic apoptosis, which contribute to abnormal alveolar development. Aim 3 will determine whether blockade of leukocyte function can safely preserve normal alveolar development during recovery from severe oxidant stress. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CHEMOKINES IN LUNG DISEASE OF HIV1 TRANSGENIC MICE Principal Investigator & Institution: Jolicoeur, Paul; Professor; Clinical Research Institute of Montreal 110 Pine Ave W Montreal, Timing: Fiscal Year 2001; Project Start 07-JUL-1999; Project End 30-JUN-2004 Summary: The long term objective of the research proposal is to study the role of chemokines and their receptors in the pathogenesis of lymphocytic interstitial pneumonitis which develop in transgenic mice expressing some of the HIV-1 genes in specific immune cells (immature CD4+CD8+ T cells, mature CD4+ T cells and cells of the macrophage/dendritic lineage. Our central hypothesis is that this lung disease is immune-mediated and is driven by the recruitment of immune cells in the lung through the action of specific chemokines. In humans infected with HIV-1 and having lymphocytic interstitial pneumonitis, the main population of immune cells found in the lung are the CD8+ T cells. Because the lung lesions of these Tg mice are associated with many other phenotypes very similar to those found in humans infected with HIV-1, we postulate that this model of lung disease is relevant to the lymphocytic interstitial pneumonitis associated with HIV-1 in humans, especially in children. To understand the pathogenesis of this lung disease, we intend: 1- To identify and quantitate the immune cells in the lung. 2- To determine whether these mice exhibit a specific lung microenvironment favoring homing of specific immune cells. 3- To identify the chemokines produced in the lung of these Tg mice. 4- To determine whether blocking or deleting specific chemokines or their receptors and overexpressing some chemokine receptors alter the development of lymphocytic interstitial pneumonitis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CHRONIC LUNG INJURY AFTER PREMATURE BIRTH Principal Investigator & Institution: Albertine, Kurt H.; Professor of Pediatrics; Pediatrics; University of Utah 200 S University St Salt Lake City, Ut 84112

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Timing: Fiscal Year 2001; Project Start 29-SEP-2000; Project End 31-AUG-2004 Summary: (Adapted from the Investigator's Abstract): Bronchopulmonary dysplasia is a complication of prolonged mechanical ventilation after premature birth. To study the pathophysiology of this disease, the investigator has developed an animal model of BPD, following premature delivery of lambs, and 3 weeks of mechanical ventilation. Utilizing this model, physiologic, biochemical, histologic, and molecular techniques will be used to determine (1) if incomplete lung development is essential for the vascular and structural abnormalities of the pulmonary circulation that occur in chronic lung disease, (2) if inhaled nitric oxide will enhance the NO-cGMP cascade and facilitate postnatal regression of vascular smooth muscle in these lambs, and (3) if decreased availability of L-arginine and/or increased activity of cGMP-specific PDE contributes to the sustained elevation of PVR and the abnormal postnatal regression of vascular smooth muscle in these premature lambs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLARA CELL SECRETORY PROTEIN IN LUNG INFLAMMATION Principal Investigator & Institution: Corry, David B.; Assistant Professor of Medicine; Medicine; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): The long- term objectives of this laboratory are to elucidate the immunopathologic basis of airway obstruction in a murine model of asthma. This proposal will investigate the role the epithelium plays in allergic lung inflammation and focus specifically on an epithelium- derived immunoregulatory molecule, Clara cell secretory protein (CCSP), that potentially limits deleterious allergic inflammation of the airway. Work from this laboratory has identified proteases derived from fungi and pollen as critical regulators of T helper activation and allergic inflammation. The dominant role played by proteases raises the intriguing possibility that the lung immune system has evolved mechanisms that limit tissue injury in the setting of allergic inflammation. Clara cells are non- ciliated respiratory epithelial cells that secrete one of the most abundant proteins contained in the respiratory lining fluid, CCSP. Although the biological functions of CCSP remain unclear, it is an antiprotease potentially capable of neutralizing exogenous proteases implicated in allergic airway disease. CCSP may also regulate adaptive immune responses of the airway by influencing epithelium-derived factors necessary for growth and survival of T and B cells. Studies from this laboratory provide preliminary evidence that CCSP downregulates airway Th2 responses provoked by exogenous proteases. Thus, CCSP is immunosuppressive with regard to allergic lung inflammation but its precise mechanisms of action remain uncertain. Aim 1 of this proposal will define the allergic settings relevant to CCSP- dependent regulation. We will investigate whether the potency of both protease- containing and protease- deficient (ovalbumin/alum) allergens is inhibited by CCSP in vivo. The role of CCSP will be evaluated using mice overexpressing CCSP in the airway and CCSP-deficient mice. In part based on the results of Aim 1, we will dissect in Aim 2 the major mechanism by which CCSP attenuates allergic inflammation. We will focus specifically on T cell-dependent effects and explore, with and without CCSP, T helper effector differentiation in vitro and in vivo, Th2 homing to lung and Th2 activation and cytokine production in vitro. Where effects are observed, we will correlate immunosuppressive activities with the antiprotease potential of CCSP. Finally, we will explore the potential of CCSP in the prevention and amelioration of allergic lung disease. Mice will be challenged intranasally with recombinant CCSP during immune induction with protease-

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containing allergens and following established allergic lung inflammation to evaluate these two endpoints. Efficacy of CCSP will be compared to a specific protease inhibitor, streptomyces subtilisin inhibitor (SSI). Together, these data will elucidate an epitheliumdependent immunomodulatory mechanism of the lung mediated through CCSP, and potentially identify novel means for the therapy of allergic lung disorders such as asthma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CLARA CELLS, THEIR SECRETIONS IN LUNG IMMUNOREGULATION Principal Investigator & Institution: Stripp, Barry R.; Associate Professor; Environ & Occupational Health; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2005 Summary: (provided by applicant): Even though cytokine production by cells of the immune system can significantly impact epithelial cell function, little is known of reciprocal roles for epithelial cells in regulation of the immune system. This is a significant issue when trying to understand the complex series of events that lead to deteriorating lung function among individuals with chronic inflammatory and/or immunological lung diseases such as COPD and asthma. There is a growing recognition that the conducting airway epithelium is dynamic in its function and that chronic lung disease results in predictable changes to epithelial cells. Among these changes are alterations in nonciliated airway epithelial cell function, for which reduced abundance of Clara cell secretory protein (CCSP) serves as a biomarker. Whether changes to Clara cells are a cause or a nonciliated airway epithelial cells contribute to exacerbation of lung disease and a continuing decline in lung function. Our recent studies in CCSP null mice (CCSP-/-) demonstrate that Clara cells fulfill important roles in defense against environmental agents in addition to serving critical immunoregulatory functions. Central to this proposal is the observation that CCSP-/- mice have elevated local production of IgA. Moreover, expression of IgA is dramatically up regulated following in vivo endotoxin exposure of CCSP-/- but not wild type mice, demonstrating fundamental differences in B-cell responsiveness with CCSP deficiency. We hypothesize that CCSP functions to suppress the immune system through either directly or indirectly regulating local B-cell function, and that these changes in B-cell function impact innate mucosal defense. If correct, changes in Clara cell function may lead to hyperstimulation of the local immune response which, although beneficial with respect to the acute clearance of colonizing microorganisms, could exacerbate airway disease and dysfunction. Aims will address four specific aspects of altered lung function that accompanies CCSP deficiency: 1) does CCSP deficiency result in altered innate and/or adaptive immunity, 2) are changes in lung immunoregulation and innate defense directly related to loss of CCSP, 3) are differences in innate defense with CCSP deficiency directly related to altered B-and/or T-cell function, and 4) which cell types are most sensitive to CCSP-dependent alterations in endotoxin signaling. By addressing these aims we will define mechanisms by which CCSP deficiency leads to altered immunoregulation within the lung. This knowledge may help in the development of strategies to block inappropriate immunological responses that lead to deteriorating lung function among individuals with chronic lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COLLABORATIVE PROGRAM IN BPD Principal Investigator & Institution: Coalson, Jacqueline J.; Professor of Pathology; Southwest Foundation for Biomedical Res San Antonio, Tx 782450549 Timing: Fiscal Year 2001; Project Start 20-JUL-1994; Project End 31-MAY-2004 Summary: The overall goal of this cooperative research program is to develop a multiinstitutional research effort to address the mechanisms of postnatal lung pathobiology that lead to chronic lung disease and to provide a unique resource center of prematurely delivered baboons with induced bronchopulmonary dysplasia (BPD) and chronic lung disease (CLD) to outstanding investigators from multiple institutions dedicated to sharing collaborative protocols and tissue specimens. In recent years, the original form of BPD described in the 1960's has become less common due to improvements in oxygenation and ventilatory strategies and the use of postnatal exogenous surfactant, and has been replaced by a less severe from of disease primarily in extremely small immature infants, called chronic lung disease of infancy (CLD). The baboon models of BPD and CLD are unique in the world; they develop disease that is very similar, if not identical, of human disease but in a controlled environment. The Southwest Foundation for Biomedical Research and the University of Texas Health Science Center at San Antonio have the breeding colony and the scientific personnel to support the proposed BPD Resource Core. The specific aims of the BPD Resource Core are: 1) To breed baboons to produce pregnancies of known gestational ages, and to delivery by caesarian section 100 timed pregnancies per year, to provide the premature infants that will be shared by multiple investigators. 2) To maintain these premature infant baboons in a neonatal intensive care environment for short periods of up to 14 days, utilizing several well-defined treatment protocols, and long-term outcomes in 1 to 2 month and 42 week survivors, the latter the baboon equivalent of a 2 year old human infant in whom alveolarization should be complete. 3) To provide tissue specimens taken at the time of delivery, during the animal's clinical course, and at necropsy in as ideal and timely a manner as possible, and tailored to each investigator's needs. 4) To provide a Data Management Core for animal information retrieval. This U-10 program brings together the enthusiasm and competence of established investigators with varying backgrounds and expertise who are committed to examining the various aspects of lung development and how, when interrupted, the fetus adapts to the extrauterine environment. It allows, at a national level, a continuing influx of outstanding scientists to address the major deficiencies in our knowledge concerning BPD/CLD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COMPLEMENT IN ALLERGIC LUNG DISEASE Principal Investigator & Institution: Wetsel, Rick A.; Professor; None; University of Texas Hlth Sci Ctr Houston Box 20036 Houston, Tx 77225 Timing: Fiscal Year 2003; Project Start 10-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): The objective of this research proposal is to delineate the overall contribution and potential mechanisms that complement utilizes to mediate the pathogenesis of allergic lung disease. The specific aims of this proposal are driven by the central hypothesis that complement activation products regulate key features of allergen-induced airway disease, including airway hyperresponsiveness (AHR) and acute airway inflammation. The results of this proposal will facilitate the evaluation of complement as a possible therapeutic target in the treatment of asthma. An allergeninduced model of pulmonary allergy in mice with specific complement deficiencies will

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be used to identify the complement pathways, activation fragments, and receptors that are potentially important in mediating the pathogenesis of allergic lung disease. The complement-deficient animals that are subjected to the model will be examined for attenuation of pathological and physiological hallmarks of asthma, including AHR, airway mucus hypersecretion, elevated IgE levels and lung eosinophils. The Th2 cytokines (IL-4, IL-5, IL-13) that have been proposed to play a pivotal role in asthma will also be examined for altered expression. In addition to the murine experimental allergic model, studies with human T-cells as well as other leukocytes isolated from patients with allergic lung disease will be used to examine potentially altered complement mediated cellular responses in asthma. Four specific aims are proposed to accomplish the research goals: 1) to examine the importance of each complement activation pathway in eliciting the asthma associated responses in an allergen-induced model of pulmonary allergy, 2) to determine how the complement anaphylatoxin receptors (C3aR and C5aR) affect the asthma associated responses in an allergen-induced model of pulmonary allergy, 3) to determine how the fifth complement component (C5) affects the asthma associated responses in an allergen-induced mouse model of pulmonary allergy, and 4) to determine the biological effects of the complement anaphylatoxins (C3a and C5a) in regulating T-cell mediated responses in asthma. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE SURVEILLANCE OF OCCUPATIIONAL HEALTH IN NEW YORK Principal Investigator & Institution: Gelberg, Kitty H.; Bureau of Occupational Health 547 River St Troy, Ny 12180 Timing: Fiscal Year 2001; Project Start 01-JUL-2001; Project End 30-JUN-2005 Summary: New York, with the assistance of the SENSOR and ABLES programs, has established a structure for occupational disease surveillance and follow-up in New York State. Provisions of the New York State (NYS) Public Health Law mandate the reporting of a number of occupational conditions in NYS. Since 1981, the New York State Department of Health, Bureau of Occupational Health (BOH) has operated a Heavy Metals Registry for the reporting of cases of lead, mercury, arsenic, and cadmium poisoning, and an Occupational Lung Disease Registry for the reporting of cases of work related lung disease. Since 1991, BOH has operated a Pesticide Poisoning Registry and receives reports from healthcare providers of suspected pesticide poisonings. While all of these registries are operational, the extent to which there is active surveillance, with aggressive case finding, ascertainment and follow-up, varies. There are a number of reasons for this variability, including differences in how the diseases are diagnosed and the different reporting sources for the various registries. Additional federal resources will permit us to build upon existing reporting laws and infrastructure and expand current surveillance efforts to help us achieve the NIOSH standards for a model core surveillance system for a range of significant occupational conditions. We propose to conduct general surveillance of existing databases available to the Department of Health such as death certificates and hospital discharge data to assist with documenting the magnitude of occupational injuries and illnesses in New York, and to identify trends and industries occupations at elevated risk. Focus will be primarily upon upgrading our Occupational Lung Disease Registry; however, we will also focus more attention on conducting educational outreach for all of our registries. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--CLINICAL Principal Investigator & Institution: Wert, Susan E.; Children's Hospital Med Ctr (Cincinnati) 3333 Burnet Ave Cincinnati, Oh 45229 Timing: Fiscal Year 2001; Project Start 01-SEP-1996; Project End 31-JUL-2006 Summary: (Applicant's Abstract) Despite recent advances in diagnosis and therapy, respiratory disease remains a major cause of morbidity and mortality in neonates and children. The specific etiologies for lung disease in this population are frequently unknown. The Clinical Core will serve as a resource for the individual program components by collecting and analyzing clinical samples pertaining to a variety of neonatal and adult pulmonary diseases, in which abnormalities of lung development and growth, surfactant function and metabolism, and/or remodeling after injury are suspected. The overall goal of these studies will be to characterize and identify mechanisms that cause idiopathic lung disease and developmental abnormalities. Dr. Lawrence Nogee, Johns Hopkins University School of Medicine, will perform genetic analyses for mutations in lung-specific genes, such as the surfactant proteins, the GMCSF Bc receptor, and TTF-1. Analysis for protein expression in frozen lung tissue, BALF, or tracheal aspirates will be performed by Dr. Jeffrey Whitsett; phospholipid analysis and surfactant function by Dr. Machiko Ikegami; and immunohistochemistry by Dr. Susan Wert, in conjunction with the Morphology Core. Analytical results will be entered into a computerized database for future reference and data analysis. As the Clinical Core identifies novel mutations in lung-specific genes, they will be tested for their capacity to cause lung disease, to disrupt surfactant function and/or metabolism, or to induce pulmonary malformations. Testing of selected mutations in vitro or in transgenic mouse models will be done in the context of each of the individual program components. These studies should enhance our understanding, of pulmonary development and pediatric lung disease, leading to the development of new treatment strategies for respiratory disorders. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CORE--INHALATION TOXICOLOGY Principal Investigator & Institution: Thorne, Peter S.; Professor; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 29-SEP-1990; Project End 31-MAR-2006 Summary: The Inhalation Toxicology Facility (ITF) consists of 6,000 square feet of contiguous laboratories and offices located in the northwest quadrant of the Institute of Rural and Environmental Health. It is secured space, with no thoroughfare, which is divided into two sections: a laboratory area and an office suite area, each with separate ventilation. This facility is the only laboratory with bona fide inhalation toxicology capabilities at the University of Iowa. A full array of inhalation toxicology, aerosol science, and bioaerosol assay services are rendered to the Center. The primary goal of the ITF is to provide facilities and expertise for EHSRC investigators with peerreviewed, funded projects and those funded through the pilot grant program to enhance the productivity and quality of their environmental health research. The facility provides assistance for new investigative efforts in pulmonary biology, inhalation toxicology, and aerosol science. This facility is designed to assist in testing hypotheses in the following areas: pulmonary biology of environmental lung disease, development and prevention of environmental lung disease, and physicochemical properties and behavior of bioaerosols, aeroallergens, and other airborne toxicants. The facility is equipped for generating and quantifying a variety of aerosols, gases, and vapors for

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exposure by whole-body or nose-only inhalation exposure routes to experimental animals in short-term and long-term exposure protocols. The facility includes a wide range of equipment for exposure, aerosol generation, aerosol monitoring and sampling, pulmonary function monitoring, and necropsy analytical equipment. Eight specific aims are outlined for this facility: 1. Provide consultation and services to Center investigators interested in using animal models for environmental health research; 2. Perform acute, subacute, and sub-chronic inhalation exposures (and sham exposures) on groups of rodents, with rigidly controlled gases, vapors, aerosols, or combined exposures using nose-only or whole-body exposure systems; 3. Establish animal biomarkers of exposure or biomarkers of effect to identify early biologic responses, low-dose functional changes, and susceptibility or host resistence factors; 4. Expand the capability for measurement of sensitive physiologic end points; 5. Develop innovative animal models for investigating or identifying potential causal agents of disease, for developing novel inhalation therapies, or for studying the behavior of aerosols in vivo; 6. Develop improved aerosol and bioaerosol sampling and analysis methodology using new analysis systems; 7. Develop novel bioaerosol identification and quantification methodology through application of new developments in molecular biology; 8. Facilitate predoctoral and postdoctoral training. In summary, the ITF provides the EHSRC with a facility with expertise in inhalation toxicology and aerosol physics, particularly for organic dusts and bioaerosols. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORE--PULMONARY BIOLOGY Principal Investigator & Institution: Hunninghake, Gary W.; Professor and Director; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 29-SEP-1990; Project End 31-MAR-2006 Summary: The Pulmonary Biology Core is headed by Gary Hunninghake, M.D.; Joel Kline, M.D., is the co-director. The focus of this core is on Environmental Lung Disease and the development of new science related to this area. The specific aims of the core are (1) to function as a training environment for young scientists interested in environmental lung disease (ELD) associated with agricultural exposures; (2) to support the research of young scientists to develop independent studies related to ELD associated with agricultural exposures; (3) to attract senior scientists to develop studies on ELD associated with agricultural exposures; (4) to consult with scientists pursuing studies related to ELD; (5) to enhance communication among investigators interested in ELD; and (6) to promote the use of dedicated EHSRC facilities for investigation of ELDs associated with agricultural exposures. The director and co-director of the core propose to meet on a monthly basis with the investigators of the Core. The purpose of these meetings will be to identify new investigators who can direct their careers to ELD. The leaders of this core also will organize bimonthly seminars to discuss ongoing research, and they will evaluate and support meritorious requests for pilot studies. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CTGF IN LUNG FIBROGENESIS Principal Investigator & Institution: Lasky, Joseph A.; Associate Professor of Medicine; Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2001; Project Start 05-JUN-2001; Project End 31-MAY-2005 Summary: (Applicant's Abstract): The formation of scars within the lungs (pulmonary fibrosis) frequently leads to shortness of breath, disability and even death. The clinical

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outcome for the vast majority of patients with idiopathic pulmonary fibrosis (IPF) remains poor. It is likely that identification of specific disease mechanisms at the molecular level will provide the best avenue for development of novel therapies. One of the key cytokines in lung fibrosis is transforming growth factor beta 1 (TGF-beta1). TGFbeta1 expression is upregulated in several models of fibroproliferative lung disease. We propose that TGF-beta1's stimulatory effect on interstitial matrix accumulation is mediated through a novel cytokine, connective tissue growth factor (CTGF). CTGF is a newly described peptide that shares several profibrogenic activities with TGF-beta1, namely as a promoter of collagen and fibronectin synthesis, as a mitogen for mesenchymal cells, and as an inducer of cell adhesion. A recent investigation has shown that the CTGF gene promoter contains a TGF-beta1 response element. We have found that CTGF upregulates lung fibroblast alpha 1 type I collagen expression in vitro and that CTGF expression is upregulated during the development of fibrosis in the two animal models of lung fibrosis that we have studied. Our recent manuscript is the sentinel description of CTGF expression during lung fibrogenesis. The overall goal in this proposal is to directly test the hypothesis that: Connective tissue growth factor is a prominent regulator of collagen deposition in fibrotic lung disease. To test our hypothesis we will demonstrate the effect of recombinant CTGF on several key facets of type I collagen synthesis and degradation in vitro. We will determine, using CTGF transgenic mice and a CTGF adenoviral vector, whether overexpression of CTGF within the lung results in pulmonary fibrosis, both alone and in the presence of other fibrogenic cytokines. We will also employ the novel approach of using a hammerhead ribozyme in vitro and in vivo to study the effect of inhibiting CTGF synthesis on TGF-beta-mediated collagen synthesis and degradation. These studies will establish the role that CTGF plays in lung fibrogenesis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CYTOKINE GENE REGULATION IN BERYLLIUM DISEASE Principal Investigator & Institution: Newman, Lee S.; Professor; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: Inhaled environmental toxins can exert effects on the lungs by altering the function of key genes. In particular, hypersensitivity immune responses to metals, such as beryllium (Be), occur when moderate cytokine and growth factor expression. The consequences are granulomatous inflammation and fibrosis. The ability to find effective treatments of environmental lung diseases, such as chronic beryllium disease (CBD), will depend upon our understanding of molecular mechanisms underlying environmentally-induced regulation of immune cell gene function. T lymphocytes and macrophages accumulate in the lungs of CBD patients. Upon Be-stimulation in vitro, CBD lymphocytes proliferate and bronchoalveolar lavage (BAL) cells produce high levels (ng/ml) of TNF-alpha and IFN-gamma. We recently found that the -308 A TNF promote polymorphism is a functional polymorphism associated with high levels (>1.5 ng/ml) of Be-stimulated CBD/BAL cell TNF- alpha protein and that these high TNFalpha levels correlate with disease severity in CBD. TNF-alpha is a pro-inflammatory cytokine important to granuloma formation in the lungs but the precise molecular mechanisms cytokine important to granuloma formation in the lungs but the precise molecular mechanisms by which Be regulates the production of high TNF-alpha levels our unknown. Our data shown that IFN-gamma priming of macrophages leads to enhancement of Be-induced TNF-alpha. Using a mouse macrophage cell line (H36.12j) that mimics the CBD macrophage response we found that Be up-regulates TNF-alpha

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protein and mRNA. Be-stimulation did not up-regulate nuclear transcription factors. However, Be+ IFN-gamma co-stimulation significantly enhances TNF-alpha production and increased nuclear levels of NF-kappaB, AP-1 and CREB. Preliminary data suggest that isolated CBD/BAL macrophages can produce lower but significant amounts of Bestimulated TNF-alpha in the absence of BAL CD4+ T cells and without IFN-gamma. The central hypothesis of this study is that: 1) Be-antigen recognition (sensitization) alone does not result in CBD. 2) CBD results when Be triggers TNF-alpha over-expression. 3) TNF-alpha over- expression occurs because IFN-gamma and Be work in concert to upregulate TNF-alpha mRNA splicing and to increase nuclear transcription factors. 4) TNF-alpha over-expression will be highest in people who have the -308 A, TNF promoter polymorphism because IFN-gamma up- regulated transcription factors enhance TNF gene transcription in the presence of the polymorphism. Together with Beinduced mRNA splicing, high TNF-alpha levels will be produced. The objective of our study is to test these specific hypothesis using isolated CBD macrophages and macrophage cell lines. We will determine whether the key control subjects cells that do not make Be-stimulated TNF-alpha. We will determine if the -308 A promoter polymorphism in concern with the TNF gene 3' untranslated region (3'UTR), stabilizes Be-stimulated TNF-alpha mRNA transcripts, thus boosting TNF-alpha protein expression. With improved understanding of the cellular and molecular mechanisms that result in progression of macrophages from the BeS to CBD phenotype, we hope, in the future, to design preventative strategies to modulate disease in high-risk, exposed individuals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DETERMINANTS OF PANCREATIC INJURY IN CYSTIC FIBROSIS Principal Investigator & Institution: Accurso, Frank J.; Professor of Pediatrics; Children's Hospital (Denver) 1056 E 19Th Ave Denver, Co 80218 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2005 Summary: (provided by applicant): Marked phenotypic variability in individuals with cystic fibrosis (CF) who have the same CF genotype suggests that modifier genes may play a role in this disorder. Since most abnormalities in CF begin early in life, investigation of determinants of disease in infants and young children may provide insight into pathogenesis. We have observed that circulating immunoreactive trypsinogen (IRT) levels in infants with CF identified through newborn screening are correlated with early pancreatic dysfunction and with pulmonary function at six years of age. IRT is therefore a biochemical marker of early pancreatic disease in CF also carrying implications for early pulmonary disease. In addition, we have observed that IRT is heritable. We therefore hypothesize that early IRT abnormalities in CF are explained in part by genes that modify the CFTR gene effect on pancreatic injury. We will test this hypothesis in infants and young children with cystic fibrosis diagnosed through newborn screening. IRT will be modeled with age using longitudinal mixed effects approaches with a log transformation to produce a quantitative phenotype that will be used in a Transmission Disequilibrium Test (TDT) to determine if IRT is cosegregating with each of the candidate modifiers. Specific modifiers to be tested can be categorized as follows: a. Genetic markers lying within the D19S112 region on chromosome 19 that have been linked to intestinal disease in CF, b. Genes coding for pancreatic enzymes that are capable of causing local tissue injury, c. Genes coding for pancreatic proteins capable of modulating local tissue injury, d. Genes coding for pancreatic membrane transporters, and e.Putative modifier genes of other CF organ involvement. Candidate genes with common, known functional variants will be studied

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through genotyping. Genes with no known functional variants will be sequenced in a subset of patients exhibiting either "rapid" or "slow" decline in IRT to identify potentially useful mutations or polymorphisms. Sequences of interest will then be examined in the entire study population, with priority as follows: obvious mutations (for example nonsense, frameshift and splice type), then promoter or missense alleles, then variants non- randomly segregating among the IRT "rapid" or "slow" decliners, and then more common variants. We also plan to establish a clinical database and a DNA repository for infants identified by newborn screening. Achieving our goals will likely provide: 1. Insight into the mechanisms of early pancreatic injury, 2. Clues to the pathophysiology of other organs involved in CF, 3. Valuable prognostic information for counseling families of newly diagnosed infants, 4. Information useful for future investigation of the pancreatic complications of CF in later life including recurrent pancreatitis and cystic fibrosis related diabetes. Our long-term objectives are to find new approaches to the early treatment of CF in order to delay pancreatic injury and the development of lung disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EISOSANOID IMBALANCE IN FIBROTIC LUNG DISEASE Principal Investigator & Institution: Peters-Golden, Marc; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2002; Project Start 26-DEC-2001; Project End 30-NOV-2006 Summary: (Applicant's Abstract) A growing body of evidence indicates that elcosanoid metabolites of arachidonic acid modulate the inflammatory, immune, and mesenchymal components contributing to pulmonary fibrosis. However, leukotrienes (LTs) promote all of these processes while prostaglandin E-, (PGE2) generally suppresses them. Of note, our laboratory has identified two separate abnormalities in eicosanoid synthesis in the lungs of patients with the fibrotic disease, idiopathic pulmonary fibrosis: namely, overproduction of LTs and underproduction of PGE2- Moreover, additional recent studies indicate that a similar eicosanoid imbalance characterizes animal models of pulmonary fibrosis, and that modulation of this imbalance by genetic or pharmacologic means attenuates fibrogenesis. The hypothesis of this proposal is that this pro-fibrotic imbalance of eicosanoid generation is centrally important in the pathogenesis and prognosis of pulmonary fibrosis. Furthermore, we hypothesize that this eicosanoid imbalance is exacerbated by treatment with corticosteroids, contributing to the disappointing clinical response of fibrotic lung diseases to these agents. The aims of the current proposal are to extend our understanding of the cellular and enzymatic mechanisms underlying this imbalance, its amenability to pharmacologic and/or genetic modulation, and the cytokines and (growth factors regulated by eicosanoids which influence the evolution of fibrotic lung disease. This will be accomplished by studying lung tissue and cells (macrophages and fibroblasts) from mice with bleomycin induced pulmonary fibrosis and from patients with pulmonary fibrosis. In the clinical studies proposed, eicosanoid abnormalities will be correlated with clinical severity, histologic classification, and course of disease. In addition, we will determine the effects of three treatment regimens for pulmonary fibrosis (prednisone, azathioprine plus prednisone, or the LT synthesis inhibitor zileuton) on eicosanoid synthesis, pathobiological mechanisms, and clinical outcomes. The proposed studies will critically evaluate a new pathophysiologic paradigm with important implications for therapy of this devastating group of fibrotic lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: ENZYMATIC DEFENSE, INFLAMMATION AND CHRONIC LUNG DISEASE Principal Investigator & Institution: Kourembanas, Stella; Associate Professor of Pediatrics; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-JUL-2006 Summary: (Applicant's Abstract) Chronic lung disease (CLD) of the preterm infant is characterized by a chronic fibroproliferative process associated with inflammation and disruption of normal alveolarization. Multiple cytokines and chemokines have been linked to the chronic inflammatory response leading to the development of CLD in humans as well as in animal models of this disease. Collaborative efforts from the group have shown that exposure of mice to extremes of oxygen tension (from 10% to 95% oxygen) resulted in lung injury characterized by a pronounced inflammatory response with mononuclear cell infiltration and dramatic induction of inflammatory cytokines/chemokines. Of interest, hypoxic mice overexpressing heme oxygenase-1 in the lung were completely protected from both inflammation as well as pulmonary vascular remodeling, a later consequence of hypoxia. Moreover, induction of inflammatory cytokines/chemokines was drastically suppressed in HO-1 transgenic mice. In this section of the SCOR application, the investigators propose 3 specific aims to extend these studies: In Aim 1, they will characterize the developmental response of the lung to injury leading to CLD. Using the newborn mouse model, they will characterize the inflammatory and architectural changes in response to hyperoxia, hypoxia, and infection that lead to CLD-like injury and analyze the effects of HO-1 induction in these developmental responses. In Aim 2, the investigators will investigate signaling pathways and molecular mechanisms by which HO-1 modulates cellular inflammatory responses. Using molecular biological techniques, they propose to analyze specific kinase pathways and transcriptional activities mediating cellular responses to injury. In Aim 3, the investigators characterize potential crosstalk between HO-1 signaling and CLD-relevant pathways in collaboration with SCOR investigators. Using transgenic mice or knockout models characterized by each member of the SCOR, they will investigate mechanisms of airway hyper-responsiveness in response to hypoxia, hyperoxia and infection; evaluate the role of chemokines in the animal models of CLDlike injury; and validate the animal findings to human disease by correlating HO activity with incidence, severity and complications of CLD in ventilated premature newborns. In achieving these aims, they will gain a better understanding of the immature lung?s defenses to injury and may be able to identify specific genes and pathways to target therapy for CLD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: EPITHELIAL GROWTH FACTORS IN ENVIRONMENTAL LUNG DISEASE Principal Investigator & Institution: Brody, Arnold R.; Professor; Pathology and Laboratory Medicine; Tulane University of Louisiana New Orleans, La New Orleans, La 70112 Timing: Fiscal Year 2001; Project Start 30-SEP-1997; Project End 31-AUG-2002 Summary: This proposal focuses on the molecular mechanisms for inhaled inorganic particle-induced fibroproliferative lung disease (FLD). The central hypothesis being examined is that interstitial fibrogenic lung disease is mediated by the mesenchymal cell growth factors, PDGF, TGF-alpha, TGF-beta and TNF-alpha, that are synthesized and secreted by the bronchiolar-alveolar epithelium as a result of lung injury. Four

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specific aims are given to test this hypothesis. In aim 1, two strains of mice resistant to the fibrogenic effects of inhaled asbestos are used to determine if the temporal and anatomic expression of the genes and growth factors by the alveolar epithelium correlates with resistance. In aim 2 alveolar epithelial cells are isolated from these same mice strains to determine if the asbestos-resistance phenotype is maintained in vitro. In aim 3 the principal investigator proposes to focus on PCNA expression in cells capable of forming fibrogenic lesions versus those from resistant mouse strains. In aim 4 transgenic mice overexpressing human PDGF-B within the bronchiolar-alveolar epithelium and spontaneously developing fibroproliferative abnormalities in the lung will be crossed with asbestos-resistant strains to determine if the offspring have increased susceptibility to asbestos. This would implicate PDGF-B in fibrogenic lung disease and target this growth factor for antibody or gene therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FAMILY BASED ANALYSIS OF MODIFIERS OF CF LUNG DISEASE Principal Investigator & Institution: Levy, Hara; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Cystic fibrosis (CF) is an inherited multisystem disease characterized by progressive deterioration in lung function and pancreatic insufficiency attributed to dysfunction of a single gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Although CF is considered a monogenic disorder, phenotype expression is considerably diverse even in patients with the same CFTR mutation. Patients with the most common mutation, delta 508 a deletion of a phenylalanine at position 508 of CFTR, often have markedly different clinical courses; some, have less aggressive lung disease and survive into their 50s, while others have a precipitous decline in lung function and die of respiratory failure in their early 20s. What accounts for this phenotypic heterogeneity is unclear. The goal of this proposal is to identify non-CFTR candidate genes that may impact the severity of CF lung disease and account for phenotypic heterogeneity. Any modifier gene identified will have important implications for defining the pathophysiology of CF lung disease, stratifying patients, and identifying new targets for therapy. To initially test our hypothesis, we propose to evaluate candidate genes that are immune-related and non-CFTR genes. Our strategy will use a family based association analysis to test for association of candidate genes to severity of pulmonary disease. We propose to combine new genotyping technology, well-powered samples, and a haplotype-based approach to comprehensively and definitively determine variation in the most promising candidate genes modifying CF lung disease. A unique contribution of this research will be the examination of genetic modifiers in CF in parent child-trios to evaluate polymorphisms in genes that may impact phenotype and hence CF lung disease. The overall hypothesis to be tested is that polymorphisms in genes associated with a well-defined phenotype represent modifying factors that account for the variability in expression of CF lung disease as measured by lung function, forced expiratory volume in one second (FEV1), in patients with the delta 508 genotype. To test this global hypothesis, we have established three specific aims: 1) Establish and characterize a CF database and define key features of the quantitative and qualitative components of our CF phenotype; relate phenotype to variation in disease severity as defined by levels of FEV1 adjusted for age and gender in CF patients homozygous for delta F508 CFTR allele. 2) Genotype single nucleotide polymorphic markers (SNPs) from five promising genes (selected based on data from Aim 1, the PGA, microarray analysis, and the literature) found to be

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associated with lung function in a sample of 100 individuals homozygous for delta 508 and identify common haplotypes and htSNPs that tag these haplotypes for these genes. 3) Genotype these htSNPs identified in AIM 2 in a sample of homozygous delta F508 individuals and their parents, and perform family based association analysis for CF phenotype and pulmonary function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE MODIFIERS IN CF LUNG DISEASE Principal Investigator & Institution: Knowles, Michael R.; Professor; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-2001; Project End 31-AUG-2006 Summary: (provided by applicant): Patients with cystic fibrosis (CF) display a wide range of disease severity, particularly in pulmonary phenotype. Although some of this variability can be attributed to specific mutations within the CFTR gene (allelic heterogeneity), much of this variability has not been adequately explained. The central hypothesis of this proposal is that much of the "severity" (or "mildness") of CF lung disease reflects the influence of non-CFTR "modifier" alleles (genes). This project is designed to identify associations between non-CFTR genes and the pulmonary phenotype. To accomplish this goal, we will study 600 CF patients who have the same CFTR genetic background, i.e., homozygous deltaF508, and who are at the extremes of pulmonary phenotype, i.e., the most severe and mildest lung disease. Pulmonary disease severity (or mildness) will be quantitated by longitudinal lung function analysis with informative censoring. The overall strategy will be to test for the association of candidate modifier alleles (genes) with the severity (or mildness) of - pulmonary disease. Key clinical features (gender; age-at-diagnosis; sweat Cl; nutrition; and respiratory microbiology) will be important variables in the overall analysis. Initially, we will test candidate genes (n=200) that have been implicated in the pathophysiology of CF lung disease. We will utilize a pooling strategy to expedite the first rounds of testing. After pooling DNA from the "severe" patients, and pooling DNA from the mild patients, we can identify those genes (alleles) with the greatest association with phenotype. Follow-up genotyping in individual subjects will allow subgroup analyses (gender; age-at-diagnosis; nutrition; respiratory microbiology) for each gene, as well as more complex analyses to search for interaction among different alleles. Subsequent studies will involve genome-wide testing with SNPs to identify loci (and genes) that are not present in the initial list of candidate genes. Identification of genes that modulate the severity of the pulmonary phenotype will improve our understanding of the pathophysiology of CF lung disease, and identify new targets for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GENETIC EPIDEMIOLOGY OF GLUTATHIONE AND CF LUNG DISEASE Principal Investigator & Institution: Mckone, Edward; Medicine; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-AUG-2007 Summary: (provided by applicant): This proposal is a five-year training plan designed to prepare the Principal Investigator for a career as an independent patient-oriented researcher with an interest in the genetic epidemiology of lung disease. Through the

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completion of these projects as well as the pursuit of course work in clinical and genetic epidemiology, the candidate will develop the necessary skills to design and implement family-based genetic association studies, including gene-gene and gene-environment interaction. The proposal is a collaboration between the Division of Pulmonary and Critical Care Medicine and the Departments of Public Health Genetics and Environmental Health and includes experts in cystic fibrosis, genetic epidemiology, environmental health and toxicology. The primary scientific goal of this research is to analyze the genetic determinants of lung disease variability in patients with cystic fibrosis (CF). Aim 1 will be a retrospective cohort study, using the National CF database, to quantify the effect of CF genotype on CF clinical manifestations, including lung function and mortality. Aim 2 will be a prospective study to examine for linkage and association between severe CF lung disease and a candidate gene that influences glutathione synthesis. DNA will be collected from CF patients and their biological parents. Transmission disequilibrium testing (TDT) will be performed on the trios looking for unequal segregation of glutayl-cysteine-ligase catalytic subunit (GLCLC) polymorphisms from parents to CF patients with severe lung disease. Aim 3 will examine for an association between severe CF lung disease and polymorphisms of glutathione-S-transferase M1 and TNF-alpha also using a TDT. As these polymorphisms may influence glutathione synthesis and function, gene-gene interaction with GLCLC polymorphisms will be examined using a case-only study design and logistic regression. Finally, in aim 4, through the use of validated questionnaires and methods of residence location, environmental exposure to tobacco smoke and air pollutants will be measured to test for gene-environment interaction. These projects have strong clinical and public health implications both in terms of predicting high-susceptibility patients that may develop severe lung disease as well as increasing our understanding of the mechanisms of CF lung function decline. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC MODIFIERS OF CYSTIC FIBROSIS Principal Investigator & Institution: Boyle, Michael P.; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2003; Project Start 04-JUL-2003; Project End 30-JUN-2008 Summary: (provided by applicant): Dr. Michael Patrick Boyle is an Assistant Professor in the Pulmonary and Critical Care Division of the Johns Hopkins School of Medicine. He is fully committed to an academic career investigating genotype and phenotype relationships in cystic fibrosis (CF). The mentor of this application, Dr. Garry Cutting, is a world-recognized expert in the genetics of CF, professor and director of graduate education at the McKusick-Nathans Institute of Genetic Medicine, and previous mentor of numerous successful K awards. The didactic and mentoring program outlined in this application is the result of close collaboration between Dr. Boyle and Dr. Cutting and will provide the foundation for Dr. Boyle's development as an independent investigator. CF is caused by mutations in the chloride channel CFTR. A wide range of severity of pulmonary disease is seen in CF individuals with identical CFTR genotypes, making it clear that CFTR genotype is not the main determinant of severity of CF lung disease. The overall goal of this proposal is to help identify the basis for variability of CF lung disease in individuals with identical CFTR genotype. We aim to answer: Do genes which modify the severity of CF lung disease exert their influence by altering the level of expression and function of CFTR, or through mechanisms unrelated to the underlying CFTR defect (e.g. inflammatory mediators, airway defense)? To do this we will determine if there is a difference in CFTR expression and function in the airway

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epithelium of homozygous delta F508 CF patients with mild and severe lung disease. First, we will use Nasal Potential Difference Measurement, the most sensitive in-vivo measurement of the ion-transport function of CFTR, to determine if there are differences in CFTR ion-transport. Second, because some cellular functions of CFTR are not reflected in these ion transport measurements, we will evaluate for differences in CFTR expression by comparing mRNA levels. These ion-transport and mRNA studies should allow us to determine if variability in CF lung disease is associated with alterations in level of expression and function of CFTR. Last, we will evaluate three of the strongest current CF candidate modifier genes to determine if the distribution of their functional alleles segregates with severity of lung disease in our CF clinic population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC RISK FACTORS FOR AIRFLOW OBSTRUCTION AFTER HSCT Principal Investigator & Institution: Clark, Joan G.; Professor; Fred Hutchinson Cancer Research Center Box 19024, 1100 Fairview Ave N Seattle, Wa 98109 Timing: Fiscal Year 2002; Project Start 16-SEP-2002; Project End 31-AUG-2004 Summary: (provided by applicant): Bronchiolitis obliterans syndrome (BOS), a clinical syndrome of irreversible, progressive airway disease causing obstructive lung disease (OLD), is a serious complication of hematopoietic stem cell transplant (HSCT). Research investigating the pathogenesis of BOS suggests that this form of OLD is immune mediated and consistent with pulmonary graft versus host disease (GVHD). Since proinflammatory and anti-inflammatory cytokines play a significant role in the pathophysiology of GVHD and the production of these cytokines is influenced by environmental and genetic factors, we believe there are genetic determinants other than histocompatibility disparity that influence the risk of developing OLD after HSCT. This project will develop a new collaborative effort between investigators in lung medicine and immunology and genetic epidemiologists to utilize an existing source of stored DNA and a novel haplotypic approach in exploring the hypothesis that allelic haplotypes of genes in the lipopoly-saccharide (LPS) inflammatory pathway influence the risk of developing OLD after HSCT. Aim 1 will assess for the association of susceptibility as well as protective allelic haplotypes of genes in the LPS inflammatory pathway in both diseased as well as hypernormal individuals. The allelic haplotypes will be generated using the Phase program developed at the University of Washington. These haplotypes are generated by selecting for single nucleotide polymorphisms (SNPs) with an allele frequency ?10% that exist in significant linkage disequilibrium with each other. When multiple such haplotypes are considered for each gene, a nonbiased analysis of nearly the entire gene can be performed for association with a complex disease. Aim 2 will confirm the association and linkage of certain allelic haplotypes of the genes in the LPS inflammatory pathway with OLD using an established family-based study design, the transmission disequilibrium test. Father, mother, and proband offspring trios will be identified in our DNA resource for genotyping to determine if haplotypes found to be significantly associated with OLD in aim 1 are indeed genetically linked and associated with disease in a family based analysis. Use of allelic haplotypes will provide an unbiased look for association with disease throughout the entire gene and an opportunity to perform rigorous fine genetic mapping and gene discovery. Ultimately, this insight can be applied to understand inflammation and how it causes more common lung diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GM-CSF IS REQUIRED FOR MACROPHAGE SURFACTANT CATABOLISM Principal Investigator & Institution: Bonfield, Tracey L.; Cleveland Clinic Foundation 9500 Euclid Ave Cleveland, Oh 44195 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Idiopathic pulmonary alveolar proteinosis (PAP) is a rare lung disease of unknown etiology. PAP is characterized by the accumulation in the alveoli of surfactant material, which is thought to result from inefficient catabolism by alveolar macrophages and type II epithelial cells. The granulocyte macrophage-colony stimulating factor (GM-CSF) knockout mouse develops a PAP like syndrome, which can be resolved by pulmonary expression of GM-CSF. These observations led to the treatment of PAP patients with recombinant GM-CSF with a subset showing improvement of lung disease. Subsequently, it was determined that all untreated PAP patients had neutralizing antibodies against GM-CSF. In this context, PAP is an excellent disease model to illustrate surfactant catabolism and lung homeostasis as well as the dynamic relationship between the "bench" and the "bedside." Further, the integration of observations in the GM-CSF knockout mouse, to ex vivo studies at the bench, to dynamic in vivo PAP patient management decisions is an excellent foundation for the development of an independent "patient-oriented" scientist. In the GM-CSF knockout mouse, it has been shown that GM-CSF regulates monocyte/macrophage surfactant catabolism through the transcription factor PU.1. GM-CSF can induce activation and differentiation of monocyte/macrophages through peroxisome proliferator-receptor (PPAR() which has not been evaluated in alveolar macrophages. Our preliminary data shows that (1) anti-GM-CSF titer is diagnostic for PAP and it correlates with PAP disease activity in vivo (2) PAP alveolar macrophages ex vivo express less PU.1 and PPAR( than healthy control alveolar macrophages, (3) PAP alveolar macrophages ex vivo express less of differentiation markers CD14, TLR2, TLR4 and MR while the expression of certain pro-inflammatory cytokines GM-CSF, IL-6 and MIP-1a are elevated as compared to healthy controls. Based upon these data, we hypothesize that maturation and differentiation of human alveolar macrophages by GM-CSF through the activation of PPAR( and PU.1 is essential for surfactant catabolism. The specific aims are: (1) Evaluate the role of GM-CSF in regulating PPAR( and PU.1 in alveolar macrophage maturation, differentiation and surfactant catabolism; (2) To use the ongoing GM-CSFFDA clinical trial to evaluate changes in functional GM-CSF on monocyte/macrophage maturation, differentiation and surfactant catabolism. The translational focus of this proposal provides an ideal training environment for the development of "patientoriented" investigative skills. Laboratory observations will be interfaced with patient clinical course, thus contributing to dynamic patient management decisions. These studies are the first to address the role of GM-CSF in alveolar macrophage maturation, differentiation and surfactant catabolism and have the unique advantage of utilizing PAP patients involved in a FDA approved GM-CSF clinical trial as an in vivo model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GROWTH FACTORS AND SIGNALING PATHWAYS IN PF Principal Investigator & Institution: Worthen, G Scott.; Associate Professor and Senior Faculty m; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2003; Project Start 19-SEP-2003; Project End 31-AUG-2007 Summary: (provided by applicant): Pulmonary fibrosis is an idiopathic interstitial lung disease with high mortality. The illness is characterized by abnormal intraparenchymal

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deposition of collagen, with focal accumulations of fibroblasts, myofibroblasts and young connective tissue that are found in unique locations within the affected lung. We propose that aberrant responses of fibroblasts to growth factor and cytokine signaling underlie the progression of disease, and may represent appropriate targets for therapy and markers of response. Using a combination of broadbased techniques, the gene expression patterns of lungs and fibroblasts from patients with pulmonary fibrosis and controls will be discerned using novel algorithms allowing analysis of many thousands of genes per sample. Expression not only of relevant gene products but also signals reflecting response to growth factors and cytokines will be measured in tissue microarrays, where a single protein will be examined in hundreds of tissue samples. The activation state of distinct lung cellular compartments, defined in a fashion not previously feasible in tissue samples from human disease, will be mapped in patients and controls. The secretion of distinct proteins that reflect fibroblast origin and response to stimulation will be pursued both in vitro, but also using bronchoalveolar lavage as a window on secretion by lung cells. New proteomic techniques to enhance throughput and reduce variation will allow elucidation of BAL-derived proteins that reflect disease behavior. The result will be a set of targets plausibly involved in excessive fibroblastic response to signals, and in vitro evidence as to the potential success of intervention strategies. New biomarkers reflecting prognosis, nosology, and response to therapy will be discerned, potentially improving the yield of new trials. The data should advance our ability to treat and monitor pulmonary fibrosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HOST-PATHOGEN INTERACTIONS IN CYSTIC FIBROSIS Principal Investigator & Institution: Moskowitz, Samuel M.; Pediatrics; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2001; Project Start 05-AUG-2001; Project End 31-JUL-2006 Summary: (provided by applicant): The goal of this application is to establish the independent research career of the candidate in the study of chronic lung disease, including that affecting individuals with cystic fibrosis (CF). The candidate is a pediatric pulmonary fellow with the career goal of developing an active program of diseaserelated basic research as a faculty member at a medical school. The training environments are the laboratory of the sponsor, Dr. Samuel Miller, at the University of Washington School of Medicine, and the CF Center at Children's Hospital and Regional Medical Center in Seattle, directed by the co-sponsor, Dr. Ronald Gibson. The proposed project seeks to clarify molecular mechanisms underlying chronic lung infection and inflammation in individuals with CF. The opportunistic pathogen Pseudomonas aeruginosa (PA) infects the lungs of most individuals with CF, frequently (but not invariably) causing severe progressive lung injury and premature death. Study of the interaction between PA and the CF lung is necessary to understand both the cellular processes that promote or permit CF lung infection, and the precise means by which PA interacts with lung cells to cause airway damage. The structure of lipopolysaccharide (LPS), the principal constituent of Gram-negative bacterial surfaces, appears to play a pivotal role in both microbial and human aspects of this interaction. The candidate's preliminary results indicate that resistance of laboratory and clinical isolates of PA to antimicrobial peptides (key components of host innate immunity) correlates with alterations in the structure of the lipid A moiety of LPS. Moreover, mutation of a PA locus that regulates LPS-modifying enzymes influences the antimicrobial peptide resistance phenotype. The microbiological phase of the project thus seeks to define PA genes necessary for this putative resistance mechanism, and to identify potential

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inhibitors using antimicrobial peptide-resistant strains. The human phase of the project builds on the clinical observation that some individuals with a severe CF genotype and chronic PA airway infection nevertheless have minimal lung disease. A case-control design will be utilized to test the hypothesis that polymorphisms in innate immune genes may limit CF lung disease. Those innate immune genes encoding the LPS receptor are leading candidates as CF modifier loci, based on the recent finding that CFspecific PA LPS structures have increased inflammatory activity. When prevalence of an LPS receptor variant differs in mild and severe CF lung disease, receptor function will be assayed in cell culture models of LPS signaling. Identifying innate immune genes as modifiers of the CF lung phenotype may suggest new avenues for treating the inflammatory consequences of CF airway infection. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMAGE AND MODEL BASED ANALYSIS OF LUNG DISEASE Principal Investigator & Institution: Hoffman, Eric A.; Professor; Radiology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-AUG-2004 Summary: With the emergence of innovative interventions in lung disease both at early and end stages of the disease (i.e.: retinoid therapy or lung volume reduction surgery for emphysema and receptor blocking therapies for lung cancer), it has become clear that sensitive, objective, accurate and repeatable measures must be developed to determine presence and regional distribution of lung abnormalities. Standard pulmonary function tests are inadequate for the task. While x-ray CT has been accepted as the most likely single modality providing a comprehensive regional lung assessment, visual scoring of the radiographs have proven to be inadequate, given the requirements of objectivity, repeatability and sensitivity. As helical scanners emerge with the ability of acquiring multi-slice data sets in less than a heart beat, the possibilities of assessing both structure and function simultaneously further limits the utility of a visual image assessment. We propose a Bioengineering Research Partnership, bring together a team of Engineers, Scientists, and Physicians from 6 academic institutions to collaborate in developing the technologies which will allow for the use of dynamic, volumetric x-ray CT to assess the lung. At the core of the research program will be a state-of-the-art helical CT facility that will evolve over the course of the proposal towards true dynamic volumetric imaging capabilities. We propose to develop a model of the normal human lung for three decades of adult age. This model will consist of an atlas of the normal anatomy down to the sub-lobar segments. Attached to these sub-lobar segments will be parameters of the normal range and distribution of airway, blood vessel, tissue, blood flow, and ventilation properties assessed at two standardized airway pressures. In addition, this model will provide normal ranges for image-based measures of chest wall mechanics and their coupling with regional lung compliance. Also attached to the model will be global parameters (PFT's, Broncho- Alveolar Lavage, exhaled Nitric Oxide). To assess the accuracy of such an approach, we focus on smoking related lung disease: specifically emphysema and cancers with assessment focused both in patients with known disease as well as in a comparison of nonsmokers and smokers with normal pulmonary function tests. The accuracy of the individual measures to be developed under this proposal will be verified in normal animals using both isolated and in-vivo lungs and using a dog model of emphysema. We hypothesize that such a comprehensive model, based upon measurements from non- invasive, dynamic, volumetric imaging can be built for the human lung and applied to the early, preclinical assessment of lung abnormality. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: IMMUNOGENETIC AND EXPOSURE FACTORS IN BERYLLIOSIS Principal Investigator & Institution: Maier, Lisa A.; National Jewish Medical & Res Ctr and Research Center Denver, Co 80206 Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-AUG-2007 Summary: The interplay between exposure and genetic susceptibility has not been defined for many disease processes. This project will focus on exposure and genetic factors which result in beryllium disease, serving to better define risk factors in this disease process, while also providing a model of gene and environment interactions for other environmental lung disease. Inhalation of beryllium particular triggers sensitivity to beryllium (BeS) and the granulomatous lung disease chronic beryllium disease (CBD) in 2-10% of exposed workers. A polymorphism in the human leukocyte antigen (HLA) DPB1 containing a glutamic acid at amino acid position 69 (Glu69), has been found in 85-97% of CBD cases compared to 30-45% of beryllium exposed non-diseased (Be-nondiseased) controls. Preliminary data show that Glu69 is also associated with BeS, suggesting that Glu69 plays a role in the immune response to beryllium, not the development of disease per se. It is likely that BD is a multi-genetic disease, with a number of susceptibility factors determining BeS, CBD and more progressive forms of CBD. To date, information on other genetic susceptibility factors is limited, as is the relationship between genes and exposure. Preliminary data presented in this proposal indicate that high TNF-alpha levels, associated with an exaggerated immune response in CBD and more severe disease, are related to the TNF promote variant with an A at position -308 (-308A). The central hypothesis of this study is that immune susceptibility factors, including Glu69 and the -308A TNF promoter variant, interact with each other and with exposure factors in the development of BeS, CBD and more severe CBD. Preliminary data support the hypothesis that by increasing beryllium-stimulated TNFalpha to high levels at the anatomical site of disease, the 308A allele may tip the scale in the direction allele may tip the scale in the direction of granulomatous inflammation, eventually resulting in progression from BeS to CBD and more severe diseases. The proposed study will determine if there is an interaction between the polymorphism associated with the development of the beryllium specific immune, Glu69, and a polymorphism associated with an increased inflammatory response via TNF-alpha, the 308 variant. Furthermore, this project will define exposure variables important in the development of BeS and CBD, and the relationship between these exposure variables and the Glu69 and -308A susceptibility genes in BeS and CBD risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INFLAMMATION IN THE CF LUNG Principal Investigator & Institution: Davis, Pamela B.; Professor; Pediatrics; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001; Project Start 01-SEP-1998; Project End 31-AUG-2003 Summary: This SCOR has its ultimate goal the cure of cystic fibrosis (CF). The studies proposed are based on the premise that understanding the origin and control of the inflammatory response in the CF lung is critical for CF therapeutics at many stages of the disease. It is our hypothesis that inflammation occurs early in the course of the CF lung disease, and must be controlled in order for other treatments to achieve maximum effectiveness. Six projects revolved around this central theme. In project 1 (P. Davis, project leader) CF mice and cell lines expressing the CF phenotype are used to explore the relationship between the CF phenotype and the inflammatory response to the most common infecting organism in CF- Pseudomonas aeruginosa. Dr. Prince's project 2 will

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investigate the activation by calcium of NF-kappaB, which is a central molecule in the inflammatory response. This transcription factor is activated by pseudomonas and regulates many of the inflammatory responses observed in CF, and appears to be activated in the basal state in some patients with CF. How calcium regulates NF-kappaB and how it participates in the pathogenesis of the CF lung disease is the focus of her project. Dr. Drumm's project 3 investigates potential modifier genes for CF that he has identified in mice and will identify in man, and will study not only how they affect salt transport but also how they affect the ability of the animal to respond to an infectious stimulus. Dr. Berger's project 4 investigates the role of the anti-inflammatory cytokine IL-10 in the pathogenesis of the CF inflammatory lung disease, and evaluates IL-10 as a possible therapeutic intervention. In collaboration with Dr. Konstan, he will investigate the inflammatory response early in life in CF infants and young children, as well as using animal models to determine the nature and pathophysiologic importance of this cytokine. Dr. Ferkol's project 5 will capitalize on what we have learned about the epithelial cell as a modulator and regulator of the inflammatory response and will test novel therapeutic approaches to the protection of the surface of the epithelial cells. Dr. Tosi's project 6 will investigate the relationship between the infection and inflammation in the CF lung and the effectiveness and toxicity of adenoviral mediated gene therapy. These projects will be supported by an Administrative Core and an Animal Core, directed by Dr. Richard Woychik, and will draw on other cores and investigators from the Cystic Fibrosis Research Center at Case Western Reserve University. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INFLAMMATION, MATRIX DISRUPTION AND CHRONIC LUNG DISEASE Principal Investigator & Institution: Ekekezie, Ike; Children's Mercy Hosp (Kansas City, Mo) 2401 Gillham Rd Kansas City, Mo 64108 Timing: Fiscal Year 2001; Project Start 07-SEP-1999; Project End 31-AUG-2004 Summary: This application seeks five year funding for the K-23 Award: PatientOriented Research Career Development. The principal investigator, Ikechukwu I. Ekekezie, M.D., is currently Assistant Professor of Pediatrics, University of MissouriKansas City School of Medicine, Attending Neonatologist, Children's Mercy Hospital, Kansas City. The mentor for this proposal is William E. Truog, M.D., Professor of Pediatrics, University of Missouri Kansas City School of Medicine. The overall objective of this proposal is to provide the necessary support for the evolution of Dr. Ekekezie's career from that of a new productive investigator into an independent physician scientist investigating pathogenesis and treatment of chronic lung disease of prematurity. The application brings together three elements: 1) an able and active clinician-candidate for research career development (Dr. Ekekezie); 2) a superb physical and intellectual environment for clinical and applied research; and 3) the most common, but poorly understood, neonatal pulmonary disorder remaining: chronic lung disease of prematurity (CLD). The improvement in mortality afforded by prenatal corticosteroid and by post-natal surfactant therapy has increased the prevalence of CLD. No current therapy, such as anti-elastase or antioxidant therapy, appears to reduce significantly the severity of CLD. Comprehensive understanding of its pathobiology is lacking. Dr. Ekekezie is currently investigating the use of inhaled nitric oxide to ameliorate CLD. He has a supplement to R-01 HL58125, which has funded his studies examining inflammation and matrix injury in CLD. He has helped design a complex clinical trial as a proposed Co-Investigator for a trial currently under review (R-01 HL62514). He has developed expertise in the biology of extracellular matrix proteins including laminin,

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and in pro-inflammatory cytokines and their contribution to the evolution of CLD. The clinical study proposed for this application is to examine the disruption of the basement membrane and extracellular matrix by metalloproteinases (MMPs) in CLD and to examine the effects of nitric oxide and corticosteroid therapy on MMP activity in CLD. Therapy with anti-MMP agents may then be studied. Appropriate use of potential new therapies will necessitate evaluation of timing, dosage, side effects, and interactions with concomitant therapies. The often unhappy history of therapeutics in neonatology demands that the most critical thinkers available use their skills in the application of new treatments to sick newborn infants. The investment in Dr. Ekekezie represented by this Award - coupled with his own enthusiasm, skills, intelligence, and high oral standards -- ought to result in his being propelled into the next generation leadership group in this area. The K-23 Award mechanism is an ideal way to advance him from here to there. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INHALED NO FOR THE PREVENTION OF CHRONIC LUNG DISEASE Principal Investigator & Institution: Kinsella, John P.; Pediatrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2001; Project Start 29-SEP-2000; Project End 31-AUG-2004 Summary: Inhaled nitric oxide (iNO) therapy is a safe and effective treatment for term newborns with persistent pulmonary hypertension and hypoxemic respiratory failure. However, little is known about the potential role of iNO in the treatment of premature newborns with respiratory failure. Premature newborns are particularly susceptible to the adverse effects of ventilator- induced lung injury, oxygen toxicity, and lung inflammation which contribute to the development of chronic lung disease (CLD). Despite treatment with exogenous surfactant and steroids, CLD remains a major cause of morbidity and mortality in premature newborns. Early clinical observations suggest that low-dose iNO improves oxygenation and decreases the need for mechanical ventilator support in the premature infant. In addition to its effects on gas exchange, recent laboratory and clinical observations suggest that iNO may also act as a lungspecific anti- inflammatory treatment and reduce the contribution of lung inflammation to the evolution of acute and chronic lung injury in premature infants. We recently conducted a masked, randomized, controlled pilot study of low- dose iNO in premature newborns with severe hypoxemic respiratory failure. Eighty patients from 12 centers were randomized to treatment with iNO (5 ppm) or placebo. Low-dose iNO caused acute improvement in oxygenation and reduced ventilator days. Moreover, important trends in CLD reduction were noted in this pilot trial, without an increased incidence of adverse events (e.g. intracranial hemorrhage). Based on the beneficial effects of iNO on gas exchange and lung inflammation, we hypothesize that early treatment with lowdose iNO may reduce the incidence of CLD in premature newborns with respiratory failure. To test this hypothesis, we have designed a multicenter, randomized, controlled, masked trial without crossover. Specific aims of this study are to determine if: l) iNO reduces CLD in premature newborns (gestational age