CHRONIC BRONCHITIS 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., 1960Chronic Bronchitis: 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: 0-497-00244-2 1. Chronic Bronchitis-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.
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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 chronic bronchitis. 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 CHRONIC BRONCHITIS ............................................................................. 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Chronic Bronchitis ........................................................................ 6 E-Journals: PubMed Central ....................................................................................................... 36 The National Library of Medicine: PubMed ................................................................................ 37 CHAPTER 2. NUTRITION AND CHRONIC BRONCHITIS ................................................................... 83 Overview...................................................................................................................................... 83 Finding Nutrition Studies on Chronic Bronchitis....................................................................... 83 Federal Resources on Nutrition ................................................................................................... 84 Additional Web Resources ........................................................................................................... 85 CHAPTER 3. ALTERNATIVE MEDICINE AND CHRONIC BRONCHITIS ............................................. 87 Overview...................................................................................................................................... 87 National Center for Complementary and Alternative Medicine.................................................. 87 Additional Web Resources ........................................................................................................... 91 General References ....................................................................................................................... 94 CHAPTER 4. PATENTS ON CHRONIC BRONCHITIS .......................................................................... 95 Overview...................................................................................................................................... 95 Patents on Chronic Bronchitis ..................................................................................................... 95 Patent Applications on Chronic Bronchitis ............................................................................... 101 Keeping Current ........................................................................................................................ 105 CHAPTER 5. BOOKS ON CHRONIC BRONCHITIS............................................................................ 107 Overview.................................................................................................................................... 107 Book Summaries: Federal Agencies............................................................................................ 107 Book Summaries: Online Booksellers......................................................................................... 108 Chapters on Chronic Bronchitis................................................................................................. 108 CHAPTER 6. MULTIMEDIA ON CHRONIC BRONCHITIS ................................................................. 111 Overview.................................................................................................................................... 111 Video Recordings ....................................................................................................................... 111 CHAPTER 7. PERIODICALS AND NEWS ON CHRONIC BRONCHITIS .............................................. 113 Overview.................................................................................................................................... 113 News Services and Press Releases.............................................................................................. 113 Academic Periodicals covering Chronic Bronchitis ................................................................... 115 CHAPTER 8. RESEARCHING MEDICATIONS .................................................................................. 117 Overview.................................................................................................................................... 117 U.S. Pharmacopeia..................................................................................................................... 117 Commercial Databases ............................................................................................................... 119 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 123 Overview.................................................................................................................................... 123 NIH Guidelines.......................................................................................................................... 123 NIH Databases........................................................................................................................... 125 Other Commercial Databases..................................................................................................... 127 APPENDIX B. PATIENT RESOURCES ............................................................................................... 129 Overview.................................................................................................................................... 129 Patient Guideline Sources.......................................................................................................... 129 Finding Associations.................................................................................................................. 132 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 135 Overview.................................................................................................................................... 135 Preparation................................................................................................................................. 135 Finding a Local Medical Library................................................................................................ 135
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Medical Libraries in the U.S. and Canada ................................................................................. 135 ONLINE GLOSSARIES................................................................................................................ 141 Online Dictionary Directories ................................................................................................... 143 CHRONIC BRONCHITIS DICTIONARY................................................................................ 145 INDEX .............................................................................................................................................. 205
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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 chronic bronchitis 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 chronic bronchitis, 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 chronic bronchitis, 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 chronic bronchitis. 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 chronic bronchitis, 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 chronic bronchitis. The Editors
1
From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.
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CHAPTER 1. STUDIES ON CHRONIC BRONCHITIS Overview In this chapter, we will show you how to locate peer-reviewed references and studies on chronic bronchitis.
The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and chronic bronchitis, 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 “chronic bronchitis” (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
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Chronic Bronchitis
study of the NHANES III database included a study population of 13,792 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. •
Managing the Patient with Severe Respiratory Problems Source: CDA Journal. Journal of the California Dental Association. 28(8): 585-586, 588589, 591-593, 595-598. August 2000. Contact: Available from California Dental Association (CDA). 1201 K Street, Sacramento, CA 95814. (916) 443-0505. Summary: The dental management of patients with severe respiratory problems continues to be a significant challenge to the dental health care practitioner. Chronic obstructive pulmonary diseases, such as chronic bronchitis and emphysema, are the fourth leading cause of death in the United States. Asthma has increased in prevalence during the past 20 years, and the rate of death from this chronic inflammatory disease of the airways has also risen despite recent advances in medical treatments. This article reviews the pathophysiology and medical treatment modalities for these chronic pulmonary diseases. The author also discusses the recognition and management of dental patients with these diseases, including how to avoid precipitating factors that could initiate an acute episode in the dental setting. The author notes that because dentists operate at the origin of the upper airway, and many dental procedures are deemed stressful, patients with chronic respiratory diseases are at special risk. The author provides detailed suggestions for preventing and managing respiratory distress in the dental setting. The entire dental team should be familiar with the signs, symptoms, and management of an emergent episode associated with asthma or chronic obstructive pulmonary diseases. 2 tables. 41 references.
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Uncovering Lesser-Known Symptoms of GERD Source: Digestive Health and Nutrition. 4(2):6. March-April 2002. Contact: Available from American Gastroenterological Association. 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. (877) DHN-4YOU or (301) 654-2055, ext. 650. Email:
[email protected]. Summary: This article describes some of the lesser known symptoms of gastroesophageal reflux disease (GERD), which are usually separated into three groups: pulmonary (asthma and chronic bronchitis); ear, nose and throat (cough, hoarseness, changing of the voice); and other, including chest pain. The author emphasizes that any chest pain indicates the need for a complete work up, to eliminate the possibility of heart disease. In addition to heartburn, the most common symptoms of GERD are chronic cough, hoarseness, sore throat, frequent clearing of the throat in the morning,
Studies
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and asthma. Some studies suggest that up to 80 percent of adult onset asthma that is not allergy related may be caused by acid reflux, especially if the episodes are frequent at night. The author also notes that an endoscopy performed on a patient with extraesophageal symptoms will usually come back normal, and more sophisticated testing will need to be done to prove a connection. 1 reference. •
Chronic Cough Source: American Family Physician. 56(5): 1395-1402. October 1, 1997. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: This article reviews chronic cough, defined as a cough that lasts for more than three weeks, and updates readers on the current thinking regarding treatment options. The author notes that more than 90 percent of cases of chronic cough result from five common causes: smoking, post-nasal drip, asthma, gastroesophageal reflux, and chronic bronchitis. Although in most patients chronic cough has a single cause, in up to one fourth of patients, multiple disorders contribute to the cough. A stepwise evaluation in patients with chronic cough can minimize the invasiveness and expense of the work up. Initial screening of patients with chronic cough should look for smoking, occupational exposure to an airway irritant, cough-inducing medications, airway hyperresponsiveness following upper respiratory infection, chronic bronchitis, or any systemic symptoms that may indicate serious disease. Patients who are not diagnosed after an initial screening are evaluated and empirically treated in a stepwise fashion for postnasal drip, asthma, and reflux. Bronchoscopy is reserved for use in the few patients still without a diagnosis after the previous steps have been completed. 1 figure. 2 tables. 32 references. (AA-M).
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Relation Between Morbidity and Cognitive Performance in a Normal Aging Population Source: Journal of Gerontology: Medical Sciences. 53A(2): M147-M154. 1998. Summary: This journal article describes a study of the association between morbidity and cognitive performance in an aging population of 1,360 community residents who were enrolled in the Maastricht Aging Study, the Netherlands. People with evidence of stroke, chronic neurological pathology, mental retardation, or chronic psychotropic drug use were excluded. Standard neuropsychological tests were used to assess memory, sensorimotor speed, and information processing speed/cognitive flexibility. Data concerning active and total (active plus inactive) health problems were obtained from a computerized patient database, and classified according to the International Classification of Primary Care. Multiple regression analyses adjusted for age, sex, and educational level revealed that both insulin-dependent and noninsulin-dependent diabetes were negatively associated with all cognitive measures. Negative associations also were found between chronic bronchitis and performance speed, and between presbyacusia and memory. The authors conclude that some specific, relatively common diseases of older age, such as diabetes and chronic bronchitis, may contribute to the age-related decline in cognitive ability. 3 tables, 30 references. (AA-M).
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Federally Funded Research on Chronic Bronchitis The U.S. Government supports a variety of research studies relating to chronic bronchitis. These studies are tracked by the Office of Extramural Research at the National Institutes of 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 chronic bronchitis. 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 chronic bronchitis. The following is typical of the type of information found when searching the CRISP database for chronic bronchitis: •
Project Title: AIR PARTICLES CAUSE DEATH IN ANIMALS WITH LUNG DISEASE Principal Investigator & Institution: Godleski, John J.; Associate Professor; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: This project will define the effects of concentrated air particles in an animal model of chromic bronchitis. It will determine the role of concentration vs composition in producing adverse effects. The project focuses upon discovery of mechanisms of death and morbidity caused by ambient air particles in animals with pre-existing pulmonary inflammation and airway hyperresponsiveness. Specific aims are: 1) To define the extent of mortality resulting from exposure to various levels of concentrated ambient air particles (CAPs) using normal adult rats and rats with chronic bronchitis; and 2) To determine the mechanisms by which inflammation contributes to mortality and morbidity from exposure to CAPs in the rat model of chronic bronchitis, and 3) To characterize the degree of airway obstruction and hypoventilation present in rats with chronic bronchitis that could lead to increased morbidity and mortality with exposure to CAPs. To assess effects of ambient air particles, animals will be exposed using the Harvard Ambient Particulate Concentration (HAPC), a newly developed device that can increase ambient particle concentrations up to thirty times ambient levels without changing the physical or chemical characteristics of the particles. The exposed animal populations will model human populations and adverse effects including increased mortality that have been identified epidemiologically. Concentrating airborne particles for use in exposures will permit the populations studied in the laboratory to be of a size to see the modeled effect and a size unable to test mechanistic hypotheses. Exposures will take place in Boston, MA, which has a typical fine particle urban aerosol ranging from 5-15 gu/m3 with transported sulfur-containing acidic particles during the summer and local combustion product particulate in winter. With Core support, extensive physical, chemical, andmicrobiologic analysis of the exposure aerosol will be carried out with correlation between these parameters and biologic responses of the animals.
2
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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Established physiologic methods will probe airway responses and their mechanisms. Cell and molecular biology methods will test mechanistic hypotheses on the role of proinflammatory mediators in the development of morbidity and mortality. The novel application of of sophisticated techniques in our proposed studies will offer new insights into mechanisms of toxicity of ambient air particles. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AIRWAY INFLAMMATION BRONCHITIS
&
MEDIATORS
IN
CHRONIC
Principal Investigator & Institution: Knowles, Michael R.; Professor; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 01-DEC-2001; Project End 30-NOV-2002 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: AIRWAY REMODELING IN SEVERE ASTHMA Principal Investigator & Institution: Castro, Mario; Associate Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 20-SEP-2001; Project End 30-JUN-2006 Summary: (provided by applicant): The overall goal of this proposal is to better understand the molecular basis for airway remodeling in children and adults with severe asthma and how it differs from mild-to-moderate asthma. In that context, we propose to study a well characterized cohort of subjects with severe asthma at baseline and two years later and contrast these findings to mild-moderate asthma, normal controls, and diseased controls (chronic bronchitis). We propose that individuals with severe asthma have more severe airway remodeling and inflammation than subjects with mild-to-moderate asthma and normal controls and that the remodeling is associated with less reversible airflow obstruction. Airway remodeling appears to develop in asthma due to a complex interaction between acute and chronic airway inflammation, insults to the airway (due to infections/toxins/environmental exposures), and underlying genetic susceptibility. Ongoing airway inflammation, epithelial desquamation/denudation (due to death or apoptosis), and repair processes, such as epithelial hyperplasia (cellular proliferation) and subepithelial fibrosis, result in abnormal structural changes in the airway. In subjects with severe asthma, this may manifest clinically as irreversible airflow obstruction and poor asthma control despite appropriate anti-inflammatory therapy. The mechanism behind this pathologic process in humans with asthma is unclear and will be better defined in this project. Furthermore, we hypothesize that a noninvasive measurement of airway wall thickness using high resolution computed tomography of the lung will correlate to the physiologic and pathologic measures of remodeling (on a segmental airway level). We will evaluate how these factors associated with remodeling are modified over time in the same individual. Accordingly, in order to better define the molecular basis for airway remodeling in severe asthma and how it differs from mild-to-moderate asthma, we propose to: (1) Define the relationship between airway remodeling and reversibility of airflow obstruction in a well characterized cohort of subjects with severe asthma; (2) Define the pro- and anti-apoptotic factors in airway epithelium associated with airway remodeling in subjects with severe asthma; and (3) Investigate whether radiologic measures of airway thickness correlate with pathologic and physiologic markers in subjects with severe asthma; and compare these findings to subjects with mild-to-
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moderate asthma and diseased and normal controls. The identification of the potential variables associated with remodeling and severe asthma will help identify individuals at risk who would benefit from specific targeted therapy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ANALYSIS OF THE AIRWAY ANTIPROTEINASE DEFENSE SYSTEM Principal Investigator & Institution: Cataltepe, Sule U.; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 01-JAN-2002; Project End 31-DEC-2006 Summary: (Adapted from applicant's abstract) Proteinases play a major role in the development of inflammatory lung diseases such as cystic fibrosis, asthma, chronic bronchitis, emphysema and chronic lung disease of prematurity. A better understanding of the regulation of proteinases by inhibitors synthesized by the lung itself could facilitate efforts to develop specific treatments for these diseases. Squamous cell carcinoma antigens (SCCA) 1 and 2 are members of the high molecular weight serine proteinase inhibitor (serpin) family. Although SCCA1 inhibits lysosomal cysteine proteinases, cathepsins (cat)L,S and K, whereas SCCA2 inhibits chymotrypsin-like serine proteinases, catG and mast cell chymase. SCCA1 and SCCA2 show a tissue restricted expression pattern and are co-localized in the tracheal, bronchial and bronchiolar epithelium. In addition, target proteinases of SCCA1, catS and catK, are expressed by the airway epithelial cells. Another source of these potent elastolytic cysteine proteinases in the lung is alveolar macrophages. Based on the in vitro inhibitory profiles and distribution patterns of SCCA1 and SCCA2 in the airways, the investigators hypothesize that these two serpins protect the airways against proteinase mediated injury. The objective of this proposal is to test this hypothesis using in vitro cell culture and in vivo transgenic animal models. The specific aims of the proposed project are to: 1) characterize the deleterious effects of exogenous and endogenous cysteine proteinases catS and catK on bronchial epithelial cells in vitro, 2) determine whether SCCA1 and/or SCCA2 can protect cultured bronchial epithelial cells from the proteinase-mediated injury and isolate the target proteinases, 3) determine whether targeted expression of SCCA1 and SCCA2 can protect the airways from proteinase-mediated injury. The experimental design involves use of cell cultures in conjunction with stable transfections to overexpress SCCA1 and SCCA2. Barrier function of the airway epithelium will be studied by permeability and transepithelial resistance measurements as well as structural analysis. Affinity chromatography and co-immunoprecipation will be used to identify the target proteinases of SCCA1 and SCCA2 in proteinase-mediated injury in vivo. The rat clara cell 10kD protein promoter (CC10) will be used to target expression of SCCA1 and SCCA2 genes to the lung. Animals will be examined to determine the extent of protection against proteinase-mediated lung injury following exposure to acrolein. These studies should enhance our understanding of the mechanisms of proteinase mediated injury and whether the locally synthesized inhibitors such as SCCA1 and SCCA2 can prevent this type of damage. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: APPROACHES TO THE GENETICS OF COPD Principal Investigator & Institution: Silverman, Edwin K.; Assistant Professor; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 16-AUG-1999; Project End 30-JUN-2004
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Summary: Cigarette smoking is the major environmental risk factor for the development of chronic obstructive pulmonary disease (COPD); however, only a subset of smokers develop clinically significant COPD. In addition to the risk from smoking, subjects with severe alpha 1-antitrypsin deficiency have a major genetic predisposition to COPD; other genetic determinants of COPD have not been proven. The frequent development of COPD in individuals with alpha 1-antitrypsin deficiency has provided a foundation for the protease-antiprotease hypothesis for the pathogenesis of COPD. However, many subjects with severe, early-onset COPD are not alpha 1-antitrypsin deficient. To define the mechanisms responsible for the development of severe, early-onset COPD unrelated to alpha 1-antitrypsin deficiency, we propose a multidisciplinary study that combines field, laboratory, and analytical approaches. We will assemble a group of 140 pedigrees ascertained through probands with severe, early-onset COPD (without severe alpha 1antitrypsin deficiency) who are referred for lung transplant or lung volume reduction surgery evaluations. We will assess these probands and their relatives with spirometry (including bronchodilator response) and a questionnaire. We will obtain genotyping with highly polymorphic short tandem repeat (STR) markers at 10 cM intervals throughout the genome from the NHLBI Mammalian Genotyping Service; these genotypes will be used to assess for genetic linkage to phenotypes including FEV1, FEV1/FVC, chronic bronchitis, and bronchodilator responsiveness. In chromosomal regions with suggestive linkage from the genome screen, additional STR markers will be tested at 1 cM intervals; multipoint linkage analysis, family-based association studies, and haplotype analysis will be used to narrow the regions likely to contain genetic determinants of COPD-related phenotypes. mRNA levels of genes within these regions narrowed by fine mapping will be compared in lung tissue from early-onset COPD probands and control subjects. The results of this study could identify specific regions of the genome which are likely to contain COPD susceptibility genes and provide candidate susceptibility genes for COPD. Identification of such genetic determinants could provide insight into the biochemical mechanisms causing the variable development of COPD at all ages, allow identification of highly susceptible individuals, and lead to new therapeutic interventions for COPD. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: ASSESSING THE OCCUPATION BURDEN IN COPD Principal Investigator & Institution: Blanc, Paul D.; Professor of Medicine; Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-AUG-2004 Summary: (From applicant's abstract): The aims are to assess the population burden of occupational exposures in the prevalence of chronic obstructive pulmonary disease (COPD) and to estimate the impact of selected occupational risks on the severity of progression of COPD. COPD is common and costly. The contribution of occupational risk factors to its prevalence and progression have not been well characterized. Better delineation of these associations has been identified as a priority area for study in the NIOSH National Occupational Research Agenda. A population sample of the continental United States of those aged 55-75, supplemented by an enriched sample in geographic "hot spots" identified by NIOSH through respiratory diseases mapping, will yield 2120 subjects, of whom 400 will have COPD defined by report of chronic bronchitis or emphysema without asthma. Structured telephone interviews will assess demographics, health status, smoking exposures, and occupational histories. High risk jobs will later be coded using a job matrix system independent of subject report of specific exposures. Two hundred of those with COPD, with over-sampling of those with
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greater severity, will be followed at 12-14 months to assess health status and health services utilization, as well as decrements in quality of life. This study will provide statistically powerful estimates of the occupational association with COPD. We should be able to identify a work-related RR of 1.35 which, coupled with an exposure frequency of 20 percent, would reflect a PAR percent of 6.5 percent. In the longitudinal study component, we should be able to detect a RR>2.1 for selected occupational risk factors as predictors of outcomes occurring in at least 10 percent of the group. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: BASIS HYPERPLASIA
OF
LONG-TERM
VIRUS-INDUCED
GOBLET
CELL
Principal Investigator & Institution: Holtzman, Michael J.; Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-JUL-2003; Project End 30-JUN-2007 Summary: (provided by applicant): The long-term goal of this proposal is to understand how respiratory viral infections lead to chronic hypersecretory airway diseases like asthma. The present proposal focuses on new findings related to the role of respiratory viruses in fine development of long-term goblet cell hyperplasia. This focus derives from our studies of mice and mouse tracheal epithelial cells successively defining that paramyxoviral infection produces not only acute bronchiolitis but also triggers a chronic response with airway hyperreactivity and goblet cell hyperplasia lasting at least a year after viral clearance. This chronic response proceeds despite protection from acute airway infammation and hyperreactivity, and in contrast to allergen challenge, the chronic response persists indefinitely and is uninfluenced by IFN-gamma deficiency. Similar to allergen, the chronic response is at least partially prevented by glucocorticoid treatment. The virus-induced chronic response also exhibits genetic susceptibility allowing for the identification of candidate target genes by a combined genetic/microarray strategy. Memory for the chronic response appears to be contained in the adaptive immune system allowing for adoptive transfer in vivo and in vitro. In addition, we find similar phenotypic responses in human subjects with asthma. Thus, we propose that paramyxoviruses cause both acute airway inflammation/hyperreactivity and chronic airway remodeling/hyperreactivity phenotypes (the latter by a hit-and-ran strategy since viral effects persist after clearance). Further, each of these phenols (acute inflammation/hyperreactivity, chronic hyperreactivity, and chronic goblet cell hyperplasia) may be genetically segregated and therefore depend on distinct controls that appear critical for the development of lifelong airway diseases. Accordingly, we have the following specific aims: I. Use a mouse model of bronchiolitis to define how specific candidate genes control longterm virusinduced goblet cell hyperplasia and how immune cells mediate this response. Here, we develop a plan to identify and characterize our first candidate gene, i.e. mouse calciumactivated chloride channel (mCLCA3) as well as a specific immune cell subset, i.e., virus-specific CD8+ memory T cells. II. Use isolated airway epithelial cells to define the molecular basis for how specific candidate genes and immune cells cause goblet cell hyperplasia in coordination with Aim I. III Use healthy and asthmatic subjects in a glucocorticoid treatment-withdrawal model to define the relationship between goblet cell hyperplasia and the status of candidates from Aims I and II. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BIOLOGY OF SUBMUCOSAL GLAND STEM CELLS IN THE AIRWAY Principal Investigator & Institution: Engelhardt, John F.; Associate Professor; Anatomy and Cell Biology; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 01-MAY-1990; Project End 30-APR-2005 Summary: The identification of airway stem cells is a critical aspect in the development of gene therapies for diseases such as cystic fibrosis (CF). Furthermore, the complexities of disease pathophysiology in CF have suggested that submucosal glands may be important therapeutic targets. One approach to target this region, which is inaccessible from the airway lumen, is to facilitate gene transfer to airway stem cells responsible for submucosal gland development in utero. However, at present little is known about the biology of these stem cell targets in the airway. To this end, we propose to characterize the cellular phenotype of airway stem cells using molecular approaches that evaluate critical aspects of gene regulation important in the formation of submucosal glands. Experiments will attempt to identify and characterize the developmental pathways leading to stem cell commitment in submucosal gland morphogenesis. Such developmental mechanisms likely also play important roles in other hypersecretory diseases such asthma and chronic bronchitis, where submucosal gland hyperplasia and/or hypertrophy occur. Previous studies by this laboratory using retroviral based lineage analysis in the airway have suggested that a pluripotent surface airway epithelial stem cell compartment also has the ability to form submucosal glands. However, relatively little is currently known about the molecular phenotype of these airway stem cells. We will evaluate in detail the regulation of one particular gene, lymphoid enhancing factor-1 (Lef-1), a transcription factor known to regulate cell-fate decisions in other tissues. Recently we showed that activation of Lef-1 gene expression defines an airway progenitor/stem cell compartment at the earliest stages of epithelial commitment to form submucosal glands (ie., epithelial condensation involved in gland bud formation). Using Lef-1 as a molecular marker for this stem cell compartment, we propose to delineate pathways and transcription factors involved in its regulation using ferret and transgenic mouse models of the airway. Detailed analysis of the Lef-1 promoter will be performed using novel in vivo based model systems that include both recombinant gutted adenoviral vectors, as well as more traditional approaches involving transgenic mice. Lastly, this proposal will also attempt to evaluate mechanisms of Lef-1 action in submucosal gland morphogenesis. Of specific interest is the pathway involving wnt activation of beta-catenin, which is known to be a co-factor for Lef-1 in some, but not all, tissues. We will evaluate a possible role for the wnt pathway and beta-catenin in submucosal gland development using a novel airway specific transgenic mouse model expressing Lef-1 mutants incapable of binding with beta-catenin. Ultimately, this project will increase our understanding of stem cell phenotypes in the airway that have pluripotent capacity for submucosal gland development. Such information will undoubtedly be useful in the development of gene therapies targeting airway stem cells and submucosal glands. Additionally, an increased understanding of submucosal gland developmental mechanisms may provide new therapeutic approaches for treating submucosal gland hyperplasia and hypertrophy in hypersecretory diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: BTP1000 & THE CLEARANCE OF MUCUS FROM THE LUNGS Principal Investigator & Institution: Yeates, Donovan B.; Research Professor; Biotechplex Corporation 755 Nicholas Blvd Elk Grove Village, Il 60007
12
Chronic Bronchitis
Timing: Fiscal Year 2002; Project Start 15-JUL-2002; Project End 16-OCT-2003 Summary: (provided by applicant): Patients with chronic bronchitis, bronchiectasis, cystic fibrosis, asthmatic bronchitis and asthma have inspissated mucus and plugs of highly viscoelastic mucus. The inability to clear this mucus leads to impaired airway function and gas exchange and consequent morbidity and mortality. Present pharmacological therapies to treat such abnormalities, although widely applied in clinical practice, are inadequate and many have little or no scientific basis. BioTechPlex proposes to demonstrate the mechanisms of action and efficacy of a new therapeutic regime (BTP1000) to hydrate the airways and enhance mucociliary clearance. The specific aim of this Phase I project is to provide the preliminary data to support the novel intracellular mechanisms underlying the rationale for the use of BTP 1000 to increase airway hydration and ciliary beat frequency; factors that can be predicted to increase the clearance of secretions from the lungs. BioTechPlex will utilize its in-depth expertise in the mechanisms governing ion and water transport across epithelium and ciliary activity as well as its advanced technologies for the investigation of these airway epithelial functions. In the Phase II project the mechanisms of action of BTP1000 will be further expanded, validated and shown to substantially increase bronchial mucociliary clearance in dogs with minimal side effects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CD14 AND LPS-INDUCED INFLAMMATION IN CHRONIC BRONCHITIS Principal Investigator & Institution: Peden, David B.; Professor of Pediatrics and Center Direc; Pediatrics; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 29-SEP-2000; Project End 31-AUG-2004 Summary: (adapted from the applicants' abstract) Chronic bronchitis and COPD are characterized by chronic neutrophilic inflammation and is associated with both airway sepsis with gram-negative bacteria. Smoking is a major risk factor for development of these diseases, but only about 20 percent of smokers develop COPD. Endotoxin (ET) from gram- negative bacteria likely plays a significant role in this inflammation. Airway ET may come directly from gram-negative bacteria infecting the airway or from tobacco smoke as this is another rich source of ET. The investigators propose that responsiveness to ET also an important risk factor for development of COPD in smokers. One mechanism by which persons may be more sensitive to ET is by enhanced production of CD14, the primary receptor for ET. CD14 exists in both a cell bound form and as a soluble from in serum and airway secretions. Soluble CD14 in the airway is enhanced by acute allergic inflammation. Additionally, a C/T polymorphism has been identified at the - 159 position of the CD14 promoter gene (CD14 gene). Those persons homozygous for the T allele have been shown to have increased soluble CD14 in serum and CD14 expression on blood monocytes compared to those with CT or CC genotype. The investigators present preliminary data that demonstrates that levels of sCD14 in sputum and CD14 expression on alveolar macrophages prior to challenge with lipopolysacharride (LPS, a form of ET) correlates with neutrophil influx in sputum following inhaled LPS challenge. Also, in the nasal airway, allergen enhances granulocyte response to LPS in a fashion which correlates with local sCD14 levels. The investigators propose to examine the role that CD14 has in determining responsiveness to airway LPS and risk for COPD in smokers. First, the investigators will determine if the level of sCD14 and CD14 on macrophages is increased in volunteers with experimentally-induced and naturally occurring bronchitis and if they have increased
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neutrophil response to LPS. Second, the investigators determine if airway CD14 correlates with PMN response to LPS in normal volunteers. Third, the investigators will determine if airway CD14 levels and LPS response in healthy volunteers with the TT genotype for the CD14 gene is enhanced relative to that in those with the CC and CT genotype. Finally, the investigators will genotype cohorts of COPD patients and healthy smokers to determine if the T allele is a risk factor in development of COPD in those who smoke. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CD40 AND TGFB IN HUMAN LUNG TRANSPLANT CHRONIC REJECTION Principal Investigator & Institution: Mckee, Charlotte M.; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 16-JUL-2001; Project End 01-AUG-2002 Summary: Chronic rejection is the most important clinical problem in human lung transplantation. The underlying causes of this process (which is manifest as obliterative bronchiolitis (OB) in lung transplants) are not completely understood, but host antidonor cellular immunity has been shown to be a key factor. The CD40 costimulatory pathway is critical for optimal cellular immune responses, and evidence suggests that CD40 activity plays a major role in chronic rejection. However, the mechanism(s) by which CD40 facilitates chronic rejection are not known. CD40 signaling can induce the production of TGFbeta, a pro-fibrotic cytokine whose role in chronic rejection and organ fibrosis is well-established, in human B cells. We postulate that CD40-mediated induction of TGFbeta1 by alveolar macrophages (AM), which are important sources of this cytokine in pulmonary fibrosis, represents a mechanistic link between CD40 activity and chronic rejection. We therefore propose to study 1) indices of CD40 activity in tissues from lung transplant patients with OB and from patients with acute rejection (who are at increased risk of developing OB) and 2) the ability of CD40 signaling to induce TGFbeta1 in AM from lung transplant patients. The Principal Investigator has an extensive background in basic immunology and clinical lung transplantation. The research project outlined here will train her to integrate these elements of her background and to approach clinical problems such as chronic rejection with the combined tools of basic science and clinical research. This award will provide her with the training, resources and protected time she needs to establish a successful career as an independent investigator in lung transplant immunology. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHARACTERIZING A 5P-LINKED BHR SUSCEPTIBILITY LOCUS Principal Investigator & Institution: Ober, Carole; Professor; Human Genetics; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2002; Project Start 30-SEP-2000; Project End 31-AUG-2005 Summary: (Adapted from the applicant's abstract) Asthma is the most common chronic disease in industrialized nations, affecting >10 million people in the U.S. alone. Familial aggregation and concordance rates in monozygotic twins have suggested a genetic component to asthma. We have been conducting studies on the genetics of asthma and atopy in the Hutterites, a founder population of European origins that practices a communal lifestyle. A genome-wide screen with 564 markers (average spacing 6 cM) was completed in an extended pedigree of 717 Hutterites who were well characterized with respect to asthma, atopy, and related phenotypes. These individuals are
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Chronic Bronchitis
descendants of only 64 ancestors who lived in the early 1700's to the early 1800's. Evidence for linkage with bronchial hyperresponsiveness2 (BHR) by the likelihood ratio test extended over 30 cM on chromosome 5p, with P-values as small as 0.001. Additional evidence for linkage at this same location was evident by the transmission disequilibrium test (P=0.0061). Typing additional markers in this region identified a critical region of 2.4 cM, corresponding to 1.5 Mb of DNA, and a high risk haplotype that is over transmitted to affected individuals. In this application, we propose to characterize the 5p-linked BHR susceptibility locus in the Hutterites by positional cloning and to replicate these findings in outbred, ethnically diverse populations. We will examine single nucleotide polymorphisms (SNPs) spaced about 10 kb apart in each gene, and assess the evidence for over transmission to affected offspring with each SNP and SNP haplotypes. Associations in the Hutterites will be replicated in the outbred samples. The functional effects of associated variants will be assessed by in vitro assays as well as by genotype-phenotype studies in outbred samples that have been evaluated for asthma and atopy phenotypes. Identifying asthma or BHR susceptibility loci may identify novel pathways in asthma pathogenesis, thereby allowing for the development of new therapies and intervention strategies for these common diseases. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOKINE BIOLOGY IN BRONCHIOLITIS OBLITERANS SYNDROME Principal Investigator & Institution: Belperio, John A.; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2002; Project Start 15-MAR-2001; Project End 28-FEB-2006 Summary: (Adapted from applicant's abstract) Chronic lung allograft rejection, Bronchiolitis Obliterans Syndrome (BOS) is a chronic process that demonstrates features of dysregulated and aberrant repair of airways. This process of fibroproliferation and deposition of extracellular matrix that ultimately leads to fibro-obliteration of airways, and impaired lung function. In this proposal, the investigators hypothesize that the persistent expression of monocyte chemoattractant protein-1 (MCP-1) during an allogeneic response and recruitment and activation of mononuclear phagocytes expression CC chemokine receptor 2 (CCR2) is a pivotal event that promotes the continuum of acute to chronic lung allograft rejection. Specifically, MCP-1 production, and the recruitment and activation of CCR2 expressing mononuclear phagocytes occurs during acute rejection. Moreover, the persistent presence of MCP-1 in the allograft maintains recruitment and activation of specific populations of mononuclear phagocytes expressing CCR2. These cells have a unique pro- fibrogenic phenotype that promotes fibrogenesis of chronic allograft rejection, BOS. Understanding the interaction between MCP-1 and CCR2 during the continuum of acute to chronic lung allograft rejection, will lead to novel therapies in the treatment and prevention of BOS. This proposal ,will test this hypothesis by performing the following experiments: I) determine the time-course, magnitude of expression, and cellular sources of MCP-1, as correlated to the recruitment of monocular cells expression CCR2 in an orthotopic rat model of acute lung allograft rejection. II) determine the specific contribution of MCP-1 to the pathogenesis of acute lung allograft rejection by a strategy of depletion of MCP-1. III) determine the timecourse of MCP-1 expression, as correlated to the recruitment of mononuclear cells expression CCR2 in a murine model of BOS. B) determine the specific contribution of MCP-1/CCR2 biology to the pathogenesis of BOS by using genetic approaches for deletion of the bioactivity of MCP-1 and/or CCR2. IV) determine if CCR2 expression mononuclear phagocytes are phenotypically profibrogenic (i.e., produce higher levels of
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TGF-beta and PDGF) and promote fibrogenesis during the pathogenesis of BOS. By successfully completing these objectives, the applicants hope to have gained significant insight into the persistence of MCP-1/CCR2 biology that impacts on the continuum and transition of acute lung allograft rejection to BOS. The understanding of this pathobiology will lead to novel therapies in the treatment and prevention of chronic lung allograft rejection, BOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CHEMOKINES IN LUNG TRANSPLANTATION Principal Investigator & Institution: Medoff, Benjamin D.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 04-AUG-2003; Project End 31-JUL-2008 Summary: (provided by applicant): With the proposed Mentored Clinical Scientist Development Award the applicant will continue his investigations into basic mechanisms of lung inflammation. After two productive years in this laboratory the applicant remains firmly committed to a career in academic pulmonary medicine. The proposed research will allow the applicant to master a broad range of laboratory techniques in immunology, cell, and molecular biology. The research experience will be supplemented by a program of study of immunology and medical science. The project focuses on the development of inflammation and fibrosis following lung transplantation and the role of chemokines in these processes. After a lung is transplanted there may be several types of injury to the graft, including ischemia-reperfusion injury, acute rejection, and chronic rejection. These immune mediated injuries contribute to the development of scarring of the airways, so called bronchiolitis obliterans (BO). Over 50% of all lung transplants will develop BO after transplantation, and this remains the major cause of morbidity and mortality after lung transplantation. Neutrophils have been shown to be a prominent component of ischemia-reperfusion injury while T lymphocytes are the primary mediators of both acute and chronic rejection. The proposed project will determine which chemokines are produced after transplantation and their contribution to the development of graft injury and subsequent BO. Further experiments will manipulate chemokine or chemokine receptor expression in animal models of lung transplantation to investigate their role in the development of graft injury and BO. The applicant specifically proposes to: (1) investigate the expression of chemokines and chemokine receptors in the lung following transplantation in patients with and without acute rejection and BO; (2) investigate the role of chemokines in the development of ischemia-reperfusion injury in the airways using the murine tracheal heterotopic model of lung transplantation; (3) investigate the role of chemokines in the development of acute airway rejection and the development of BO in the murine tracheal heterotopic model of lung transplantation; (4) develop a novel murine model of airway rejection and BO. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: CHRONIC LOCALIZATION
OBSTRUCTIVE
PULMONARY
DISEASE
GENE
Principal Investigator & Institution: Hasstedt, Sandra J.; Associate Professor; Human Genetics; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Applicant's Abstract): Chronic obstructive pulmonary disease (COPD) is a slowly progressive disorder characterized by airways obstruction that lasts for at least
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several months. The two major causes of COPD are chronic bronchitis and emphysema. Either disorder may occur with or without airways obstruction, but airways obstruction causes impairment of lung function leading to disability and death. COPD is a major health problem in the United States and throughout the world, consistently ranking among the most common causes of death in the United States. Cigarette smoking is the primary environmental factor that increases the risk of COPD, but other environmental factors have also been implicated. However, despite a well-established role, environmental factors alone do not cause COPD. Symptomatic COPD develops in only 10-20 percent of heavy cigarette smokers, probably those with a genetic susceptibility, although common COPD susceptibility genes have yet to be identified. This project proposes a single specific aim: to localize, within the genome, a COPD susceptibility gene. The strategy proposed is to apply statistical linkage analysis to family data. Pulmonary measurements have already been collected on 159 members of 16 pedigrees and evidence supporting a COPD susceptibility gene in these pedigrees has been obtained from segregation analysis. Each of 11,995 genetic markers, which have already been genotyped on pedigree members, will be tested for evidence of linkage to the inferred COPD susceptibility gene. Evidence of linkage to one or more genetic markers will identify genomic locations of COPD susceptibility genes. The high density of markers will allow fine-mapping of the gene. Successful completion of this gene localization project is the necessary prerequisite for a project to identify and characterize a COPD susceptibility gene. Identifying a gene that when mutated increases the risk of COPD may increase understanding of pulmonary function, as well as allowing genecarriers to be identified and made aware of their susceptibility. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: CORE--EXPOSURE FACILITY Principal Investigator & Institution: Spengler, John; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The Exposures Facility Core has seven components: 1) Organic chemistry laboratory, 2) Inorganic chemistry laboratory, 3) Microbiology laboratory Particle measurements (aerosol properties) laboratory, 4) Metal analysis laboratory, 5) Radiation laboratory, 6) Inhalation laboratory. The aims of this core are to maintain the analytical equipment, to facilitate quality control/quality assurance programs, to provide staff and Center faculty with flexibility to develop/adopt analytical methods, and to provide training and supervision to students, postdoctoral fellows, and visiting scientists. All laboratories have written standard operating procedures and quality assurance programs, many of which include interlaboratory testing. The organic chemistry laboratory has analyzed breast milk and cord blood samples for PCBs as part of a study of the effect of low levels of PCBs on reproductive outcomes in New Bedford, and this work will be extended to examine reproductive effects of PCBs in a Russian city contaminated by PCBs. They have also participated in several interlaboratory studies. The inorganic chemistry laboratory has developed an annular denuder system and methods for studying acidic aerosols and gases, ammonia, and passive and active ozone samplers. The environmental microbiology laboratory has developed methods for assessing fungi, bacteria, endotoxin and allergens in bulk dust and air samples. The aerosol properties laboratory specializes in the generation and characterization of particles. The laboratory has developed an ambient particle concentrator for use in animal and human exposure studies. Work is currently in progress on determining the partitioning between gas and particle phase of semi-volatile organic compounds. The
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metals/aquatic laboratory has studied samples of metal exposures of workers, in sediments and biota of Boston and New Bedford harbors, and in water along the USMexican border, and arsenic in the toenails of Taiwanese as part of a study of bladder and skin cancer. A future project will study the bioavailability of heavy metals in contaminated marine sediments. The radiation biology laboratory has several unique radiation sources, including an X-ray generator, an high intensity cobalt source, and an irradiation chamber for animals. Members of the Biochemical and Environmental Toxicology and the Radiobiology and Environmental Carcinogenesis Cores have used these devices to produce "feed layers" of cells for studies of the growth of differentiated cells an tissues in vitro and in studies of DNA damage and repair. The inhalation laboratory provides researchers with the facilities and technical expertise to expose animals to various types of air pollutants, including ozone, sulfur dioxide, particles, fly ash, ethylene oxide, and cigarette smoke, and to monitor their pulmonary responses, including ventilatory parameters and pulmonary mechanics, to these exposures. Studies conducted include the examination of various mechanisms or markers of ozone induced lung injury, the role of adhesion molecules and ctytokines in epithelial injury and repair, the role of sensory neuropeptides found in C-fibers in ozone-induced lung injury and altered airway responsiveness, and the use of SO2 exposure to generate animal models of chronic bronchitis. The mechanisms of mortality and morbidity associated with urban exposure to particles is being studies by exposing dogs and rats to concentrated ambient particles. Future plans include evaluation of the role of adhesion molecules in the airway hyper-responsiveness characteristic of ozone exposure, and further work on the development of biomarkers of ozone exposure. Physiologic responses, e.g., measures of ventilation, to inhaled gases or particles can be monitored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: TOXICOLOGY
CORE--RESPIRATORY
BIOLOGY
AND
INHALATION
Principal Investigator & Institution: Brain, Joseph D.; Professor; Harvard University (Medical School) Medical School Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: The Respiratory Biology and Inhalation Toxicology (RBIT) Core has as its objective "to understand how breathing results in environmental and occupational lung disease." The core seeks to develop prevention strategies and more effective treatments for pulmonary diseases including lung cancer, asthma, pulmonary fibrosis, and emphysema. The RBIT Core is primarily concerned with the effects of inhaled environmental toxicants on the mammalian pulmonary system. The Respiratory Biology and Inhalation Toxicology Core is involved with five primary lines of investigation. First, they have investigated the mechanisms of particle binding to alveolar macrophages and epithelial cell lines. Their data suggest that the macrophage scavenger receptor system is responsible for the binding of charged particles such as latex beads and titanium dioxide as well as quartz, fly ash and urban air particulates. This system did not appear to be operative in A549 epithelial cell lines. They now wish to pursue studies of the calcium concentration dependency of this binding and inhibition of this binding by scavenger receptor ligands. They have determined that appropriately-raised polyclonal antibodies block particle binding. Thus, they would like to investigate the molecular biology of this further using scavenger receptor knock out mice and expression cloning of blocking antibodies. Lastly , they plan to study the effects of mitochondrial oxidant production on cytokine release upon exposure to quartz versus titanium. The second line of investigation seeks to elucidate the mechanism of the
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epidemiologic finding that mortality of cardiovascular etiology is elevated about 24 hours after peaks in the concentration of urban air particulates (PM10). To carry out these studies they have used the ambient air particle concentrator (a series of virtual impactors) built by Sioutas and Koutrakis, et al. to generate concentrated urban air aerosols from Boston ambient air. Animal models (dogs, rats, and mice) are used that attempt to recreate the susceptibility factors that are associated with mortality during urban air inversions. Included are a chronic bronchitis model, various knock out mice, and dogs with induced cardiac ischemia. The third research interest concerns the physiology and biology of airway hyper-responsiveness. This group has worked extensively with a technique that measures the stiffness of smooth muscle cell cytoskeleton by manipulating and measuring the effects of cytoskeleton-bound ferromagnetic spheres on magnetic fields. This technique allows Respiratory Biology and Inhalation Toxicology Core investigators to test the effects of cytokines or pharmacologic agents on the contractility of airway smooth muscle cells. They are also interested in developing mouse models for allergic inflammation and airway hyperresponsiveness. They describe their fourth area of research interest as the development and application of bioassays for lung injury. For the most part this appears to be an effort to bring published assays into the laboratory s repertoire. Assays include lavage cytokines, enzymes, proteins, and message for several mediators. The last area of investigation described for the Respiratory Biology and Inhalation Toxicology Core is studies of the molecular mechanisms of pulmonary inflammation. In this work the investigators are considering signal transduction pathways for lung cell adhesion and the dynamics of neutrophil migration into the lung. They are also investigating the cells and chemokines that trigger the release of reactive oxygen species. In particular, they have studied rat MIP-1 alpha and MIP-2, a neutrophil chemotactic chemokine. Within these research studies is evidence of collaboration between the Respiratory Biology and Inhalation Toxicology Core and several other cores and facilities within the Center. Most notable are the Environmental Epidemiology Research Core and the Toxicology Research Core although there is reference to the Occupational Health Core and the Environmental Sciences and Engineering Core as well. The Respiratory Biology and Inhalation Toxicology Core investigators rely on a number of facilities for equipment and expertise. A central molecular biology laboratory provides nucleic acid and protein sequencing, PCR, in site hybridization and immunocytochemistry. Tissue and cell culture facilities are maintained within the Physiology Program. The Bioimaging Core provides laser scanning, confocal microscopy and morphometrics capabilities. The two electron microscopy laboratories offer scanning and transmission electron microscopy with electron specrtoscope imaging capabilities. An inhalation toxicology laboratory has three 1m3 Lucite chambers and two 100 l Lucite chambers. They are primarily set-up for the generation of gases (ozone and So2) and for concentrated Boston ambient air particles. The Respiratory Biology and Inhalation Toxicology Core is equipped with devices for blood and gaseous phase gas analysis and devices for respiratory mechanics and electrophysiology. Lastly, the core has developed a device for magnetometry in order to study changes in cytoskeletal stiffness. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EPIDEMIOLOGIC STUDIES OF LUNG CANCER RISKS IN NSAID USERS Principal Investigator & Institution: Zheng, Wei; Professor; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002
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Summary: (provided by applicant): Cumulative evidence from in vitro and animal studies suggests that the enzyme cyclooxygenase-2 (COX-2) is important in the development and progression of lung cancer. Epidemiologic studies evaluating the association between the use of aspirin (an inhibitor of COX-2) and the risk of lung cancer have been conflicting, and no study has been conducted to evaluate non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs). Using pre-recorded drug prescription databases of the Tennessee Medicaid program and North Jutland County of Denmark, we propose to conduct two studies in these populations to examine the effect of NSAID use on the risk of lung cancer. The first is a retrospective cohort study of over 10,000 enrollees of the Tennessee Medicaid Program who were diagnosed with chronic obstructive pulmonary diseases (COPD) during the period of 1980 to 2002. The second is a population-based, retrospective cohort study of over 150,000 users of NSAIDs in the general population of North Jutland County during the period of 1991 to 2002. Within the Danish cohort will be a nested case-control study of 350 cases and 700 controls, in which relevant information will be obtained on over the counter (OTC) analgesic use, as well as cigarette smoking and other potential confounding factors. The two studies proposed here complement each other and provide for an international comparison of NSAIDs as possible lung cancer chemoprevention agents. Because the data on NSAID use have already been collected, the studies will be very cost-efficient. More importantly, the use of pre-recorded pharmacy records minimizes potential errors in exposure assessment and provides a major advantage over existing cohort studies in evaluating the potential chemopreventive effect of NSAIDs. Given the high incidence and mortality of lung cancer and high prevalence of NSAID use, the results from our studies may have important public health implications in lung cancer prevention, and could set the stage for future randomized trials of COX-2 inhibitors in cancer prevention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: EPITHELIAL CELL RESPONSE TO H.INFLUENZAE IN THE AIRWAY Principal Investigator & Institution: Look, Dwight C.; Professor; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 31-JUL-2004 Summary: (adapted from the application): Inflammation of the airway epithelium is often required for effective innate defense against microbes, and epithelial cells provide critical biochemical signals that regulate this response. One major mechanism that epithelial cells in the airway use to participate in the inflammatory response is through regulation of leukocyte trafficking and/or activation by expression of intercellular adhesion molecule-1 (ICAM-1). ICAM-1 serves as a ligand for leukocyte beta2-integrins and thereby mediates epithelial-leukocyte interactions that may allow for "appropriate" inflammatory responses (e.g., to a respiratory bacterial infection) or "inappropriate" responses (e.g., airway inflammation in cystic fibrosis). This proposal focuses on Haemophilus influenzae, which frequently colonizes human respiratory mucosa and often produces respiratory tract disease, particularly in patients with chronic bronchitis, bronchiectasis, and cystic fibrosis. The specific aims of this proposal are based on four observations regarding airway epithelial cell ICAM-1 expression in response to H. influenzae: 1) H. influenzae induces airway epithelial cell ICAM-1 expression in vivo and in vitro; 2) ICAM-1 expression is required for efficient bacterial clearance in a murine model of airway infection with H. influenzae; 3) increased ICAM-1 expression can be initiated by epithelial cell interaction with a constitutive molecule on the bacterial cell surface; and 4) airway epithelial cell interaction with H. influezae results in
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Chronic Bronchitis
generation of soluble ICAM-1 inducing activity containing a novel mediator(s) of ICAM1 expression. Based on these observations, they hypothesize that direct induction of specific epithelial genes (such as ICAM-l) allow for rapid targeting and/or activation of neutrophils and other leukocytes at sites of H. influenzae infection, resulting in efficient innate defense in the airway. Accordingly, there are two specific aims. 1) Define mechanisms for induction of epithelial cell ICAM-1 expression by H. influenzae. This aim will take advantage of in vitro coculture models of epithelial cell interaction with bacteria. Definition of mechanisms for ICAM-1 gene activation in response to H influenzae will be accomplished by analysis of ICAM-1 promoter function and identification of mediator molecules. This latter refers to the observation that airway epithelial cells challenged with H. influenzae release a novel soluble factor into the medium capable of eliciting ICAM-1 in naive epithelial cells. 2) Determine functions of ICAM-1 in defense against H. influenzae infection. This aim will take advantage of in vivo murine models of airway infection by bacteria. The functions of ICAM-1 will be determined by examining ICAM-1 expression, leukocyte recruitment and function, and bacteria clearance under conditions that allow for manipulation of airway defense factors. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: FUEL OIL ASH AND HUMAN HEALTH Principal Investigator & Institution: Christiani, David C.; Professor; Harvard University (Sch of Public Hlth) Public Health Campus Boston, Ma 02115 Timing: Fiscal Year 2002 Summary: Population-based epidemiologic studies of communities in the United States have revealed a consistent association between ambient particulate air pollution and increases in morbidity and mortality. The observed increases result from both respiratory and cardiovascular diseases for subjects over age 65. These ambient exposures are to levels of particulates many times lower than occupational exposures faced by workers in a variety of industries, including manufacturing, construction, transportation and electric-power generation. The objective of this proposal is to investigate the role of occupational exposure to particulates in the development of respiratory and cardiac responses in boilermakers with and without chronic bronchitis. We will employ a detailed continuous-exposure assessment to PM2.5 with repeated measures of biologic and physiologic markers of response. Specific hypotheses to be tested will include: (1) occupational exposure to fuel-oil ash particulates and associated metals induce airway inflammation as reflected in decreases in peak flow (PEFR) and FEV1; (2) particulate exposure and associated metals will result in acute changes in cardiovascular function, as reflected in changes in heart rate, heart-rate variability and blood pressure; (3) particulate metal exposure will result in increased serum fibrinogen levels, a known risk factor for cardiovascular disease; and (4) chronic bronchitis predisposes exposed workers to changes in cardiac function. The experimental approach will be an epidemiologic study employing a prospective, repeated measures design assessing several biologic parameters in relation to exposure. The expected results will clarify the relationship between exposure to oil-combustion ash metals and human cardiopulmonary responses in both normal and chronic bronchitic populations. Clarification of such exposure-response relationships will have important implications for preventive efforts aimed at reducing morbidity and mortality form exposure to respirable particulates and their associated metals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
Studies
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Project Title: IL-12 P80 MEDIATED AIRWAY INFLAMMATION Principal Investigator & Institution: Walter, Michael J.; Assistant Professor; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Asthma is characterized by an inappropriate immune response manifested as enhanced accumulation of immune cells in the airway. In general, the immune response has been divided into innate and adaptive components, and recent evidence indicates the innate immune response generates inflammatory mediators that provide critical immunomodulatory signals to the adaptive immune system. In the particular context of the inflammatory response to inhaled materials, we have proposed the airway epithelial cells represent an ideal candidate to act as a primary sentinel site in innate immunity. This possibility was derived from observations that these cells express a network of immune-response genes that provide critical immunomodulatory and biochemical signals for immune cell influx, activation, and retention in the airway. The current proposal is based on several novel findings related to a member of the interleukin (IL)-12 family, called IL-12 p80 (p80). We identified the airway epithelial cell as a novel cellular source for p80 production following cytokine administration, infection with Sendai virus, and in subjects with asthma. Furthermore, Sendai viral infection of mice that lacked another IL-12 family member (IL-12 p35) overproduced p80 and displayed inappropriate inflammation characterized by enhanced accumulation of macrophages in the airway. Interestingly, in asthma subjects, but not normal or chronic bronchitis patients, we again found p80 overproduction that correlated with enhanced macrophage accumulation. Further studies demonstrated p80 functions as a macrophage chemoattractant and the IL-12 receptor beta 1 chain (IL-12Rbeta1) is necessary and sufficient to generate this p80dependent chemotactic response. Taken together, our results associate p80 overproduction with excessive viral and asthmatic inflammation, new functional consequences of p80 production in vivo, and p80-dependent immunomodulatory properties, such as macrophage chemotaxis, that are mediated through IL-12Rbeta1 signaling. Accordingly, the aims of this proposal are to define p80-dependent macrophage accumulation following SdV infection and characterize the proteins that mediate this response. In addition, we will define the structural components of IL12Rbeta1 that mediate p80-dependent chemotaxis. These studies will provide insight into the pathogenesis of inappropriate viral and asthmatic airway inflammation, and exploitation of this knowledge will provide the framework to develop selective regulators of p80 function in order to modulate this inflammation. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: IMMUNE MECHANISMS OF REJECTION IN HUMAN LUNG ALLOGRAFTS Principal Investigator & Institution: Mohanakumar, Thalachallour; Professor; Surgery; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-AUG-1996; Project End 31-JUL-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen
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Project Title: INFLUENCE OF CRANBERRY ON PLAQUE-RELATED DISEASES Principal Investigator & Institution: Koo, Hyun; Eastman Dentistry; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627
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Chronic Bronchitis
Timing: Fiscal Year 2004; Project Start 01-JAN-2004; Project End 30-NOV-2006 Summary: (provided by applicant): Dental caries is the most common oral infectious disease that afflicts humans. More than 95% of all adults have experienced this disease. It is more common than asthma, hay fever or chronic bronchitis in 5-17 year old children. The American public spends close to $40 billion per year to treat this disease or its consequences. Dental caries results from the interaction of specific bacteria with constituents of the diet on a susceptible tooth surface. Dental plaque accumulation is the first clinical evidence of this interaction; dental plaque is a biofilm which is comprised of a population of bacteria growing on the tooth surface enmeshed in a polysaccharide matrix. Acid can be formed rapidly by acidogenic bacteria, such as Streptococcus mutans, within the matrix and its persistence results in dissolution of the tooth. Furthermore, plaque is also the major aetiological factor in gingivitis. Cranberries, like other natural products, harbor a plethora of biological compounds such as flavonoids (e.g. quercetin and myricetin), phenolic acids (benzoic acid), anthocyanins, condensed tannins, and others. We have shown that many of these substances can: (i) inhibit enzymes associated with the formation of the plaque polysaccharide matrix, (ii) block adherence of bacteria to surfaces, (iii) prevent acid formation, and (iv) reduce acid tolerance of cariogenic organisms. For example, quercetin and myricetin are effective inhibitors of glucosyltransferases (GTFs), enzymes responsible for the synthesis of glucans; glucans synthesized by GTFs mediate the adherence and accumulation of cariogenic streptococci on the tooth surface. Weak acids, such as benzoate (benzoic acid), affect the acid production by S. mutans and have been shown to reduce dental caries in rats. We propose a comprehensive plan to explore the influence of cranberry on many of the biological aspects involved in the pathogenesis of dental plaque formation and caries. We also propose to examine the ability of cranberry to prevent or reduce caries in our well-proven rodent model and to investigate the effects of cranberry on plaque formation and gingivitis in vivo. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •
Project Title: INHALED PARTICLE CHARACTERISTICS AND EARLY LUNG EFFECTS Principal Investigator & Institution: Beckett, William S.; Professor; Environmental Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAY-2004 Summary: (Adapted from the Investigator's Abstract) Chronic obstructive pulmonary disease (COPD) is a disabling condition produced by chronic bronchitis (airway inflammation and mucus hypersecretion) and emphysema (loss of alveolar surface area). Epidemiologic studies of the workplace have consistently shown an excess of COPD associated with dusty work environments, yet only a few substances (coal, silica, cadmium) causing COPD in the workplace have been characterized based on chemical composition and respirable particle size. These findings suggest that the much broader range of workplace dusts may in certain conditions contribute to COPD based on characteristics other than chemical composition alone. Pulmonary inflammation plays a role in early events leading to COPD. Particles less than 10 micron aerodynamic diameter are considered to be able to penetrate the upper airways and reach the respiratory tract, and are thus designated as being in the respirable range. Ambient fine particles (
