Lung Development and Regeneration (Lung Biology in Health and Disease)

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LUNG DEVELOPMENT AND REGENERATION

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LUNG BIOLOGY IN HEALTH AND DISEASE Executive Editor Claude Lenfant Former Director, National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland

1. Immunologic and Infectious Reactions in the Lung, edited by C. H. Kirkpatrick and H. Y. Reynolds 2. The Biochemical Basis of Pulmonary Function, edited by R. G. Crystal 3. Bioengineering Aspects of the Lung, edited by J. B. West 4. Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane 5. Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain, D. F. Proctor, and L. M. Reid 6. Development of the Lung, edited by W. A. Hodson 7. Lung Water and Solute Exchange, edited by N. C. Staub 8. Extrapulmonary Manifestations of Respiratory Disease, edited by E. D. Robin 9. Chronic Obstructive Pulmonary Disease, edited by T. L. Petty 10. Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris 11. Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin 12. The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permutt 13. Evolution of Respiratory Processes: A Comparative Approach, edited by S. C. Wood and C. Lenfant 14. Pulmonary Vascular Diseases, edited by K. M. Moser 15. Physiology and Pharmacology of the Airways, edited by J. A. Nadel 16. Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M. A. Sackner 17. Regulation of Breathing (in two parts), edited by T. F. Hornbein 18. Occupational Lung Diseases: Research Approaches and Methods, edited by H. Weill and M. Turner-Warwick 19. Immunopharmacology of the Lung, edited by H. H. Newball 20. Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B. L. Fanburg 21. Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan 22. Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. S. Young 23. Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H. L. Atkins 24. Acute Respiratory Failure, edited by W. M. Zapol and K. J. Falke 25. Gas Mixing and Distribution in the Lung, edited by L. A. Engel and M. Paiva 26. High-Frequency Ventilation in Intensive Care and During Surgery, edited by G. Carlon and W. S. Howland

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27. Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G. H. Nelson 28. Chronic Obstructive Pulmonary Disease: Second Edition, edited by T. L. Petty 29. The Thorax (in two parts), edited by C. Roussos and P. T. Macklem 30. The Pleura in Health and Disease, edited by J. Chrétien, J. Bignon, and A. Hirsch 31. Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W. Jenne and S. Murphy 32. Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan 33. The Airways: Neural Control in Health and Disease, edited by M. A. Kaliner and P. J. Barnes 34. Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke 35. Respiratory Function of the Upper Airway, edited by O. P. Mathew and G. Sant'Ambrogio 36. Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and I. Grant 37. Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T. Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams 38. Pulmonary Vascular Physiology and Pathophysiology, edited by E. K. Weir and J. T. Reeves 39. Comparative Pulmonary Physiology: Current Concepts, edited by S. C. Wood 40. Respiratory Physiology: An Analytical Approach, edited by H. K. Chang and M. Paiva 41. Lung Cell Biology, edited by D. Massaro 42. Heart–Lung Interactions in Health and Disease, edited by S. M. Scharf and S. S. Cassidy 43. Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M. J. Hensley and N. A. Saunders 44. Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky 45. The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A. Zimmerman 46. Diagnostic Imaging of the Lung, edited by C. E. Putman 47. Models of Lung Disease: Microscopy and Structural Methods, edited by J. Gil 48. Electron Microscopy of the Lung, edited by D. E. Schraufnagel 49. Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J. Barnes, and C. G. A. Persson 50. Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and F. Lemaire 51. Lung Disease in the Tropics, edited by O. P. Sharma 52. Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J. Whipp and K. Wasserman 53. Developmental Neurobiology of Breathing, edited by G. G. Haddad and J. P. Farber 54. Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H. Anderson 55. The Airway Epithelium, edited by S. G. Farmer and D. Hay 56. Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R. W. Millard 57. The Bronchial Circulation, edited by J. Butler 58. Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S. D. Bernal and P. J. Hesketh 59. Pulmonary Complications of Systemic Disease, edited by J. F. Murray

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60. Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T. J. Ferro 61. Cytokines of the Lung, edited by J. Kelley 62. The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D. Metcalfe 63. Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler 64. Cystic Fibrosis, edited by P. B. Davis 65. Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center, and V. A. Tkachuk 66. Tuberculosis: A Comprehensive International Approach, edited by L. B. Reichman and E. S. Hershfield 67. Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K. F. Chung and P. J. Barnes 68. Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg, J. P. Martin, and R. Masse 69. Pneumocystis carinii Pneumonia: Second Edition, edited by P. D. Walzer 70. Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M. Effros and H. K. Chang 71. Sleep and Breathing: Second Edition, edited by N. A. Saunders and C. E. Sullivan 72. Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T. Takishima and S. Shimura 73. Sarcoidosis and Other Granulomatous Disorders, edited by D. G. James 74. Epidemiology of Lung Cancer, edited by J. M. Samet 75. Pulmonary Embolism, edited by M. Morpurgo 76. Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach 77. Endotoxin and the Lungs, edited by K. L. Brigham 78. The Mesothelial Cell and Mesothelioma, edited by M. C. Jaurand and J. Bignon 79. Regulation of Breathing: Second Edition, edited by J. A. Dempsey and A. I. Pack 80. Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall 81. Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W. J. O'Donohue, Jr. 82. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C. O. Trouth, R. M. Millis, H. F. Kiwull-Schöne, and M. E. Schläfke 83. A History of Breathing Physiology, edited by D. F. Proctor 84. Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W. Taeusch 85. The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C. Roussos 86. Severe Asthma: Pathogenesis and Clinical Management, edited by S. J. Szefler and D. Y. M. Leung 87. Mycobacterium avium–Complex Infection: Progress in Research and Treatment, edited by J. A. Korvick and C. A. Benson 88. Alpha 1–Antitrypsin Deficiency: Biology • Pathogenesis • Clinical Manifestations • Therapy, edited by R. G. Crystal 89. Adhesion Molecules and the Lung, edited by P. A. Ward and J. C. Fantone 90. Respiratory Sensation, edited by L. Adams and A. Guz 91. Pulmonary Rehabilitation, edited by A. P. Fishman

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92. Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J. P. Derenne, W. A. Whitelaw, and T. Similowski 93. Environmental Impact on the Airways: From Injury to Repair, edited by J. Chrétien and D. Dusser 94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A. J. Hickey 95. Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G. G. Haddad and G. Lister 96. The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers 97. Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R. P. Schleimer, W. W. Busse, and P. M. O’Byrne 98. Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch 99. Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich 100. Lung Growth and Development, edited by J. A. McDonald 101. Parasitic Lung Diseases, edited by A. A. F. Mahmoud 102. Lung Macrophages and Dendritic Cells in Health and Disease, edited by M. F. Lipscomb and S. W. Russell 103. Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman 104. Gene Therapy for Diseases of the Lung, edited by K. L. Brigham 105. Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz Clerch and D. J. Massaro 106. Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M. O’Byrne 107. Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L. Adjei and P. K. Gupta 108. Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom 109. Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M. Orenstein and R. C. Stern 110. Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M. Schatz, R. S. Zeiger, and H. N. Claman 111. Dyspnea, edited by D. A. Mahler 112. Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said 113. Self-Management of Asthma, edited by H. Kotses and A. Harver 114. Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J. Gryglewski, and J. R. Vane 115. Fatal Asthma, edited by A. L. Sheffer 116. Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar 117. Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W. W. Busse 118. Physiological Basis of Ventilatory Support, edited by J. J. Marini and A. S. Slutsky 119. Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen and J. M. Beck 120. Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S. E. Dahlén, and T. H. Lee 121. Complexity in Structure and Function of the Lung, edited by M. P. Hlastala and H. T. Robertson 122. Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr. 123. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R. Durham, and N. Mygind

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124. Lung Tumors: Fundamental Biology and Clinical Management, edited by C. Brambilla and E. Brambilla 125. Interleukin-5: From Molecule to Drug Target for Asthma, edited by C. J. Sanderson 126. Pediatric Asthma, edited by S. Murphy and H. W. Kelly 127. Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F. Wright 128. Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M. Foster 129. Gastroesophageal Reflux Disease and Airway Disease, edited by M. R. Stein 130. Exercise-Induced Asthma, edited by E. R. McFadden, Jr. 131. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J. Moss 132. The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller 133. Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and P. C. Zee 134. Anticholinergic Agents in the Upper and Lower Airways, edited by S. L. Spector 135. Control of Breathing in Health and Disease, edited by M. D. Altose and Y. Kawakami 136. Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel 137. Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J. Coalson 138. Asthma’s Impact on Society: The Social and Economic Burden, edited by K. B. Weiss, A. S. Buist, and S. D. Sullivan 139. New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z. Diamant 140. Multimodality Treatment of Lung Cancer, edited by A. T. Skarin 141. Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S. Nelson and T. R. Martin 142. Diagnostic Pulmonary Pathology, edited by P. T. Cagle 143. Particle–Lung Interactions, edited by P. Gehr and J. Heyder 144. Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L. B. Reichman and E. S. Hershfield 145. Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R. J. Martin and M. Kraft 146. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T. D. Bradley and J. S. Floras 147. Sleep and Breathing in Children: A Developmental Approach, edited by G. M. Loughlin, J. L. Carroll, and C. L. Marcus 148. Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J. Roca, R. Rodriguez-Roisen, and P. D. Wagner 149. Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter 150. Nosocomial Pneumonia, edited by W. R. Jarvis 151. Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P. Barker 152. Long-Term Mechanical Ventilation, edited by N. S. Hill 153. Environmental Asthma, edited by R. K. Bush 154. Asthma and Respiratory Infections, edited by D. P. Skoner 155. Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bousquet, S. Rak, and R. A. Pauwels 156. Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad and T. Xu

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157. Respiratory-Circulatory Interactions in Health and Disease, edited by S. M. Scharf, M. R. Pinsky, and S. Magder 158. Ventilator Management Strategies for Critical Care, edited by N. S. Hill and M. M. Levy 159. Severe Asthma: Pathogenesis and Clinical Management, Second Edition, Revised and Expanded, edited by S. J. Szefler and D. Y. M. Leung 160. Gravity and the Lung: Lessons from Microgravity, edited by G. K. Prisk, M. Paiva, and J. B. West 161. High Altitude: An Exploration of Human Adaptation, edited by T. F. Hornbein and R. B. Schoene 162. Drug Delivery to the Lung, edited by H. Bisgaard, C. O’Callaghan, and G. C. Smaldone 163. Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited by R. P. Schleimer, P. M. O’Byrne, S. J. Szefler, and R. Brattsand 164. IgE and Anti-IgE Therapy in Asthma and Allergic Disease, edited by R. B. Fick, Jr., and P. M. Jardieu 165. Clinical Management of Chronic Obstructive Pulmonary Disease, edited by T. Similowski, W. A. Whitelaw, and J. P. Derenne 166. Sleep Apnea: Pathogenesis, Diagnosis, and Treatment, edited by A. I. Pack 167. Biotherapeutic Approaches to Asthma, edited by J. Agosti and A. L. Sheffer 168. Proteoglycans in Lung Disease, edited by H. G. Garg, P. J. Roughley, and C. A. Hales 169. Gene Therapy in Lung Disease, edited by S. M. Albelda 170. Disease Markers in Exhaled Breath, edited by N. Marczin, S. A. Kharitonov, M. H. Yacoub, and P. J. Barnes 171. Sleep-Related Breathing Disorders: Experimental Models and Therapeutic Potential, edited by D. W. Carley and M. Radulovacki 172. Chemokines in the Lung, edited by R. M. Strieter, S. L. Kunkel, and T. J. Standiford 173. Respiratory Control and Disorders in the Newborn, edited by O. P. Mathew 174. The Immunological Basis of Asthma, edited by B. N. Lambrecht, H. C. Hoogsteden, and Z. Diamant 175. Oxygen Sensing: Responses and Adaptation to Hypoxia, edited by S. Lahiri, G. L. Semenza, and N. R. Prabhakar 176. Non-Neoplastic Advanced Lung Disease, edited by J. Maurer 177. Therapeutic Targets in Airway Inflammation, edited by N. T. Eissa and D. P. Huston 178. Respiratory Infections in Allergy and Asthma, edited by S. L. Johnston and N. G. Papadopoulos 179. Acute Respiratory Distress Syndrome, edited by M. A. Matthay 180. Venous Thromboembolism, edited by J. E. Dalen 181. Upper and Lower Respiratory Disease, edited by J. Corren, A. Togias, and J. Bousquet 182. Pharmacotherapy in Chronic Obstructive Pulmonary Disease, edited by B. R. Celli 183. Acute Exacerbations of Chronic Obstructive Pulmonary Disease, edited by N. M. Siafakas, N. R. Anthonisen, and D. Georgopoulos 184. Lung Volume Reduction Surgery for Emphysema, edited by H. E. Fessler, J. J. Reilly, Jr., and D. J. Sugarbaker 185. Idiopathic Pulmonary Fibrosis, edited by J. P. Lynch III 186. Pleural Disease, edited by D. Bouros

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187. Oxygen/Nitrogen Radicals: Lung Injury and Disease, edited by V. Vallyathan, V. Castranova, and X. Shi 188. Therapy for Mucus-Clearance Disorders, edited by B. K. Rubin and C. P. van der Schans 189. Interventional Pulmonary Medicine, edited by J. F. Beamis, Jr., P. N. Mathur, and A. C. Mehta 190. Lung Development and Regeneration, edited by D. J. Massaro, G. Massaro, and P. Chambon

ADDITIONAL VOLUMES IN PREPARATION Long-Term Intervention in Chronic Obstructive Pulmonary Disease, edited by R. Pauwels, D. S. Postma, and S. T. Weiss Sleep Deprivation: Basic Science, Physiology, and Behavior, edited by C. A. Kushida Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects, edited by C. A. Kushida Pneumocystis Pneumonia: Third Edition, Revised and Expanded, edited by P. D. Walzer and M. Cushion Ion Channels in the Pulmonary Vasculature, edited by J. X.-J. Yuan Asthma Prevention, edited by W. W. Busse and R. F. Lemanske, Jr.

The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.

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LUNG DEVELOPMENT AND REGENERATION

Edited by

Donald J. Massaro Georgetown University School of Medicine, Washington, D.C., U.S.A.

Gloria DeCarlo Massaro Georgetown University School of Medicine, Washington, D.C., U.S.A.

Pierre Chambon Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.

Marcel Dekker

New York

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Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recom-mendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-5439-5 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc., 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc., Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more infor-mation, write to Special Sales/Professional Marketing at the headquarters address above. Copyright © 2004 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA

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Introduction Most often, advances in biology follow a very tortuous path. Lung biology illustrates this very well, perhaps better than any other system. Considerable research has been done not only to understand lung development, but also to uncover ways to accelerate it in the case of premature birth. Over the years, remarkable successes have been noted, as evidenced by the increasing survival of babies born well before their lungs are mature. This achievement is due in great part to the development of pharmacologic and instrumental interventions to accelerate lung maturation and to keep the immature lung functional until maturity is reached. On the other hand, the mature lung—the adult lung—is subject to injuries that, over time, lead to its structural alteration, a situation that culminates in emphysema. Most of the time, these alterations are the result of an excess of elastase due to exogenous factors such as cigarette smoke. Recently it has been shown that retinoic acid, a derivative of vitamin A, plays a role in the development of the lung and, conversely, that inhibition of retinoic acid results in elastase injury of the lung. The demonstration that exogenous retinoic acid can induce alveolar cell regeneration in an animal model of emphysema suggests the possibility that it could be used therapeutically in patients suffering from emphysema. Simply put, retinoic acid may be necessary not only for normal alveolar development but also for maintenance of the integrity of the alveolar surface. The mechanism of action of retinoic acid is not yet fully understood but, clearly, it somehow intervenes in the genetic machinery that leads to normal lung development. Whether or not that machinery is reactivated when retinoic acid is given to stimulate lung cell regeneration remains a major question. Bronchopulmonary dysplasia and chronic obstructive pulmonary disease are both defined by whether or not retinoic acid plays its presumed role, that is, alveolar cell generation in bronchopulmonary dysplasia or alveolar cell protection in emphysema. The public heath significance of this issue is huge, as both conditions are very prevalent in all regions of the world. This volume, edited by Donald Massaro and Gloria DeCarlo Massaro of the United States, and Pierre Chambon of France, gives the reader an opportunity to travel into the exciting field of the function and role of retinoic acid and its receptors. The editors have led the research on the role of retinoic receptors in the integrity and stability of alveolar cells in the perinatal and post-perinatal periods. They enrolled contributors who are experts highly recognized for their work in this area or other relevant fields of lung biology.

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As the Executive Editor of the series of monographs Lung Biology in Health and Disease, I highly value the opportunity to introduce this volume to the readership and thereby give readers a taste of a novel field of biology that has promising implications for clinical application.

Claude Lenfant, MD Gaithersburg, Maryland

Preface

The last decade has witnessed exponential growth of interest and work in the area of lung development, alveolar regeneration, and alveolar architectural stability. These events have led to new insights into mechanisms by which the lung develops and maintains its architecture. In particular, although lagging behind studies on development of conducting airways, interest in the formation of alveoli has grown. Old notions of the immutability of alveolar structure short of disease have given way to new concepts of alveolar plasticity, i.e., regeneration and nondisease-related loss. These ideas, supported by experiments, have given hope to the possibility that therapeutic alveolar regeneration and slowing of alveolar loss may be realistic expections over the next decade. The present volume was designed to focus on two diseases - bronchopulmonary dysplasia as an example of alveolar developmental failure, and chronic obstructive pulmonary disease, as an example of presently irremedial alveolar loss. Our aim was to present two important clinical entities and supportive experimental and technological means aimed at achieving their remediation. Donald Massaro Gloria DeCarlo Massaro Pierre Chambon v

Contents

Series Introduction Preface I.

Claude Lenfant

iii v

Diseases: Bronchopulmonary Dysplasia (BPD) and Chronic Obstructive Pulmonary Disease (COPD)

1. Arrested Alveolar Development in Bronchopulmonary Dysplasia Jacqueline J. Coalson

1

2. Bronchopulmonary Dysplasia in the Postsurfactant Era Richard D. Bland

21

3. What is Chronic Obstructive Pulmonary Disease? Robert M. Rogers

51

4. Small Airways Disease in Chronic Obstructive Pulmonary Disease James C. Hogg 5. Alveolar and Bronchiolar Inflammation in COPD Simonetta Baraldo, Graziella Turato, Bianca Beghe´, Renzo Zuin, and Marina Saetta 6. Pathophysiological Basis for the Treatment of Chronic Obstructive Pulmonary Disease Cynthia Brown and Robert A. Wise

67 99

115 vii

viii 7.

II.

8.

9.

Contents Clinical Approaches for Evaluating Retinoids as a Treatment for Human Emphysema Michael D. Roth, Jonathan G. Goldin, and Jenny T. Mao

149

Technological and Theoretical Foundations for Studies Aimed at Remedial Therapy Detecting Differentially Expressed Genes by Differential Display Yong-Jig Cho and Peng Liang

185

Expression Profiling as a Tool for Diagnosis and Pathway Discovery: Experimental Design and Technical Considerations Eric P. Hoffman, Donald Massaro, Gloria Massaro, Linda Clerch, and Yue Wang

197

10.

Plasticity of Circulating Adult Stem Cells Timothy R. Brazelton and Helen M. Blau

11.

The Mechanical and Cytoskeletal Basis of Lung Morphogenesis Eben Alsberg, Kimberly Moore, Sui Huang, Tom Polte, and Donald E. Ingber

217

247

III.

Comparative Lung Structure and Mechanics

12.

Morphogenesis of the Mammalian Lung: Aspects of Structure and Extracellular Matrix Johannes C. Schittny and Peter H. Burri

275

Structure and Function of Nonmammalian Vertebrate Lungs J.N. Maina

319

13.

IV.

Branching Morphogenesis

14.

Lung Branching Morphogenesis: Potential for Regeneration of Small Conducting Airways Minke van Tuyl, Veronica del Riccio, and Martin Post

355

Contents V.

The Gas-Exchange Region

15.

Apoptosis and Emphysema Norbert F. Voelkel, Laimute Taraseviciene-Stewart, and Rubin M. Tuder

16.

Genetic Analysis of Emphysema and Animal Models of COPD Steven D. Shapiro and Ravi Mahadeva

17.

Pulmonary Alveoli: Development, Structural Stability, and Regeneration Donald J. Massaro, Gloria Decarlo Massaro, and Linda Biadasz Clerch

ix

395

411

433

18.

Molecular Response to Pneumonectomy Leonard J. Landesberg and Ronald G. Crystal

19.

Pulmonary Limitations to Exercise Performance: The Effects of Healthy Ageing and COPD Jordan D. Miller and Jerome A. Dempsey

483

Pulmonary Adaptation to Sustained Changes in Metabolic Rate Jacopo P. Mortola

525

20.

Index

455

573

Contributors

Eben Alsberg Children’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Simonetta Baraldo Bianca Beghe´

University of Padua, Padua, Italy

Richard D. Bland ifornia, U.S.A. Helen M. Blau nia, U.S.A.

University of Padua, Padua, Italy

Stanford University School of Medicine, Stanford, Cal-

Stanford University School of Medicine, Stanford, Califor-

Timothy R. Brazelton California, U.S.A.

Stanford University School of Medicine, Stanford,

Cynthia Brown Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Peter H. Burri

University of Bern, Bern, Switzerland

Yong-Jig Cho

Vanderbilt University, Nashville, Tennessee, U.S.A. xi

xii

Contributors

Linda Biadasz Clerch ington, D.C., U.S.A.

Georgetown University School of Medicine, Wash-

Jacqueline J. Coalson University of Texas Health Science Center, San Antonio, Texas, U.S.A. Ronald G. Crystal Weill Medical College of Cornell University, New York, New York, U.S.A. Jerome A. Dempsey sin, U.S.A.

University of Wisconsin–Madison, Madison, Wiscon-

Jonathan G. Goldin David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Eric P. Hoffman U.S.A. James C. Hogg bia, Canada

Children’s National Medical Center, Washington, D.C.,

University of British Columbia, Vancouver, British Colum-

Sui Huang Children’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Donald E. Ingber Children’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Leonard J. Landesberg Weill Medical College of Cornell University, New York, New York, U.S.A. Peng Liang

Vanderbilt University, Nashville, Tennessee, U.S.A.

Ravi Mahadeva University of Cambridge Institute for Medical Research, Cambridge, England J. N. Maina

University of the Witwatersrand, Johannesburg, South Africa

Jenny T. Mao David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Donald J. Massaro ton, D.C., U.S.A.

Georgetown University School of Medicine, Washing-

Contributors

xiii

Gloria Decarlo Massaro Georgetown University School of Medicine, Washington, D.C., U.S.A. University of Wisconsin–Madison, Madison, Wisconsin,

Jordan D. Miller U.S.A.

Kimberly Moore Children’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Jacopo P. Mortola McGill University, Montreal, Quebec, Canada Tom Polte Children’s Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A. Martin Post

University of Toronto, Toronto, Ontario, Canada

Veronica del Riccio

University of Toronto, Toronto, Ontario, Canada

Robert M. Rogers University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A. Michael D. Roth David Geffen School of Medicine at UCLA, Los Angeles, California, U.S.A. Marina Saetta

University of Padua, Padua, Italy

Johannes C. Schittny

University of Bern, Bern, Switzerland

Steven D. Shapiro Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A. Laimute Taraseviciene-Stewart University of Colorado, Health Sciences Center, Denver, Colorado, U.S.A. Rubin M. Tuder

Johns Hopkins University, Baltimore, Maryland, U.S.A.

Graziella Turato

University of Padua, Padua, Italy

Minke van Tuyl

University of Toronto, Toronto, Ontario, Canada

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Norbert F. Voelkel University of Colorado, Health Sciences Center, Denver, Colorado, U.S.A. Yue Wang Virginia Polytechnic Institute, Alexandria, VA, U.S.A. Robert A. Wise Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. Renzo Zuin University of Padua, Padua, Italy

1 Arrested Alveolar Development in Bronchopulmonary Dysplasia

JACQUELINE J. COALSON University of Texas Health Science Center San Antonio, Texas, U.S.A.

I. Evolution of BPD When bronchopulmonary dysplasia (BPD) was first described in premature infants in 1967, Northway et al. speculated that its pathogenesis was a prolongation of the healing phase of severe hyaline membrane disease (HMD) combined with generalized pulmonary oxygen toxicity. They recognized that endotracheal intubation and mechanical ventilation might have contributed to the development of the disease (1). The concept that BPD is primarily a disease that results from an arrest in alveolar development has only emerged over the last two decades. As better oxygenation and ventilatory strategies were developed and utilized, the classically described lung lesions of bronchial squamous metaplasia, alternating sites of emphysema (overinflation) and severe fibrosis, and the consequences of pulmonary vascular hypertension largely disappeared. These were replaced as the result of newer studies with descriptious of what were termed simplified lung (2); a ‘‘premature lung pattern (3); an interstitial form of BPD, characterized by arrested development of terminal air spaces (4); or acinar arrest’’ (5). Classic, or what is termed old BPD, pathological findings reflected primarily the consequences of elevated oxygen and ventilator-induced injury on a relatively immature and 1

2

Coalson

surfactant deficient lung. For example, Northway et al.’s study group had an average gestational age and birthweight of 32 weeks and 1893 gr, respectively. Even before the introduction of exogenous surfactant therapy, the better clinical management and technological advances had resulted in BPD occurring primarily in infants who were born 60 mm Hg with and without nocturnal oxyhemoglobin desaturation. Chest 1992; 101:649– 655. 65. Chaouat A, Weitzenblum E, Kessler R, Charpentier C, Ehrhart M, Schott R, et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999; 14:1002–1008. 66. Chaouat A, Weitezenblum E, Kessler R, Schott R, Charpentier C, Levi-Valensi, et al. Outcome of COPD patients with mild daytime hypoxemia with or without sleep-related oxygen desaturation. Eur Respir J 2001; 17:848–855. 67. Fletcher EC, Luckett RA, Goodnight-White S, Miller CC, Qian W, Costarangos-Galarza C. A double-blind trial of nocturnal supplemental oxygen for sleep desaturation in patients with chronic obstructive pulmonary disease and a daytime PaO2 above 60 mm Hg. Am Rev Respir Dis 1992; 145:1070–1076. 68. MacNee W, Donalson K. Exacerbations of COPD: environmental mechanisms. Chest 2000; 117:S390–S397. 69. Yamamoto C, Yoneda T, Yoshikawa M, Fu A, Tokuyama T, Tsukaguchi K, Narita N. Airway inflammation in COPD assessed by sputum levels of interleukin-8. Chest 1997; 112:505–510. 70. Stockley RA. Neutrophils and protease/antiprotease imbalance. Am J Respir Crit Care Med 1999; 160:S49–S52. 71. Hunninghake GW, Crystal RG. Cigarette smoking and lung destruction: accumulation of neutrophils in the lungs of cigarette smokers. Am Rev Respir Dis 1983; 128:833–838. 72. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences of interleukin-8 and tumour necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996; 153:530–534. 73. Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med 1995; 152:1666– 1672. 74. Finlay GA, O’Driscoll LR, Russell KJ, D’Arcy EM, Masterson JB, Fitzgerald MX, O’Connor CM. Matrix metalloproteinase expression and production by alveolar macrophages in emphysema. Am J Respir Crit Care Med 1997; 156: 240–247. 75. Shapiro SD. The macrophage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999; 160:S29–S32. 76. Lucey EC, Stone PJ, Breuer R, Christensen PG, Calore JD, Catanes A, Franzblau C, Snider GL. Effect of combined human neutrophil cathepsin G and elastase on induction of secretary cell metaplasia and emphysema in hamsters with in vitro observations on elastolysis by these enzymes. Am Rev Respir Dis 1985; 132:362–366. 77. Liou TG, Campbell EJ. Quantum proteolysis resulting from release of single granules by human neutrophils. J Immunol 1996; 157:2624–2631. 78. Liou TG, Campbell EJ. Non-isotropic enzyme-inhibitor interactions: a novel

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oral glucocorticoids on inflammatory indices in asthma and COPD. Am J Respir Crit Care Med 1997; 155:542–548. Culpitt SV, Rogers DF, Shah P, De Matos C, Russell RE, Donnelly LE, Barnes PJ. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003; 167:24–31. Ito K, Lim S, Caramori G, Chung KF, Barnes PJ, Adcock IM. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001; 15:1110–1112. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen TKon behalf of the ISOLDE study investigators. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. Br Med J 2000; 320:1297–1303. Vestbo J, Sorensen T, Lange P, Brix A, Torre P, Viskum K. Long-term effect of inhaled budesonide in mild and moderate chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 1999; 353:1819–1823. Pauwels RA, Lofdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking: European Respiratory Society Study on Chronic Obstructive Pulmonary Disease. N Engl J Med 1999; 340:1948–1953. The Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med 2000; 343:1902–1909. Sin DD, Tu JV. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164:580–584. Hubbard RB, Smith CJ, Smeeth L, Harrison TW, Tattersfield AE. Inhaled corticosteroids and hip fracture: a population-based case–control study. Am J Respir Crit Care Med 2002; 166:1563–1566. Senderovitz T, Vestbo J, Frandsen J, Maltbaek N, Norgaard M, Nielsen C, Kampmann JP. Steroid reversibility test followed by inhaled budesonide or placebo in outpatients with stable chronic obstructive pulmonary disease: The Danish Society of Respiratory Medicine. Respir Med 1999; 93:715– 718. Postma DS, Steenhuis EJ, van der Weele LT, Sluiter HJ. Severe chronic airflow obstruction: can corticosteroids slow down progression? Eur J Respir Dis 1985; 67:56–64. Decramer M, de Bock V, Dom R. Functional and histologic picture of steroidinduced myopathy in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1996; 153:1958–1964. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, Anderson P, Morgan NA. Effect of systemic glucocorticoids on exacerbations

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7 Clinical Approaches for Evaluating Retinoids as a Treatment for Human Emphysema

MICHAEL D. ROTH, JONATHAN G. GOLDIN, and JENNY T. MAO David Geffen School of Medicine at UCLA Los Angeles, California, U.S.A.

I. Introduction Emphysema affects over 2 million Americans and is one of the most serious respiratory complications of cigarette smoking (1,2). The pathogenesis of this disease is complex, but an imbalance between pulmonary protease and antiprotease activity appears to be centrally involved (3,4). Protease-induced tissue destruction leads to the rupture of alveolar septa and the progressive enlargement of terminal airspaces: the pathological hallmark of emphysema (5,6). This tissue disruption directly reduces the surface area of the lung available for gas exchange and reduces inherent tissue elasticity. These anatomical and physiological changes lead over time to hyperinflation of the lungs, airflow obstruction, ventilation/perfusion mismatching, inadequate gas exchange, increased pulmonary vascular resistance, and right heart dysfunction (Fig. 1). The adult lung does not spontaneously regenerate and the destructive effects of emphysema have heretofore been considered progressive and irreversible. Current therapies primarily focus on reducing the rate of injury, reducing complications, or controlling and ameliorating associated symptoms such as cough, sputum, or bronchospasm (7,8). Lung transplantation is 149

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Figure 1 The complex pathophysiology of emphysema. An imbalance between pulmonary protease activity (favoring tissue injury) and antiprotease activity (providing tissue protection), in combination with chronic inflammation, leads to destruction of alveolar septa and a complex network of functional complications that contribute to the clinical manifestations of emphysema.

one exception to this rule, but the tremendous cost, limited supply of organs, and high morbidity and mortality keep this procedure from becoming a viable standard of care (9). Since the initial report by Cooper and associates (10), lung volume reduction surgery has attracted wide attention as a treatment modality. However, questions about its efficacy, safety, durability, cost, and risk/benefit ratio remain to be answered in clinical trials now underway. Patients with advanced and homogeneous lung disease are at a particularly high risk for surgical complications (11). Even when clinically successful, the beneficial effects of lung volume reduction decline at an accelerated rate, with 50% of patients returning to pretreatment lung function by 2–3 years after operation (12). As of this date, no available treatment directly addresses the goal of restoring protease/antiprotease balance or regenerating the structure and function of damaged lung tissue. Given the lack of effective therapy for emphysema at present, innovative research programs are needed to explore new frontiers and therapeutic options for this debilitating disease. In 1997, Massaro and Massaro reported that the administration of all trans-retinoic acid (ATRA) reversed anatomical and physiological consequences of elastase-induced emphysema in a rat model (13). This was the first suggestion that lung injury resulting from emphysema might be reversible. Similar in vivo findings were soon replicated by Belloni and colleagues (14)

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using either ATRA or 9-cis retinoic acid. Retinoids are known to activate genes involved in lung development and promote alveolar septation in the pre- and postnatal period (15–17). In the study by Massaro and Massaro (13), elastase was instilled into the lungs of adult rats to produce changes characteristic of emphysema, including enlarged terminal air spaces with ruptured septa, a decrease in alveolar number, loss of elastic tissue, and resulting hyperinflation of the lungs. After allowing time for the destructive changes to stabilize, a 12 day treatment with ATRA resulted in tissue regeneration with a significant reversal of the anatomical and physiological manifestations of the disease. No spontaneous regeneration was observed in the absence of retinoid therapy. Although findings from these animal models are exciting, caution is warranted when comparing elastase-induced emphysema with the complex pathogenesis of human emphysema (Table 1). Unlike the elastase-treated rat, in which unaffected lung tissue appeared normal, the remaining lung tissue in patients with emphysema is functionally and structurally altered. The tissue shows changes in basement membrane, pulmonary blood flow, epithelial cells, endothelial cells, and inflammatory cells (18,19). Structural and functional changes in the human lung are also heterogeneously distributed, with some areas appearing relatively normal while other areas range from minimally to severely involved with disease (20). This poses a complex challenge in

Table 1 Comparison Between Elastase-Induced Emphysema Model and Human Emphysema

Similarities

Differences

Conditions

Rat elastase model

Human emphysema

Enlarged distal airspaces Reduced alveolar number Hyperinflation Reduced gas exchange Pathogenesis Duration of injury Ongoing injury Tissue alterations Heterogeneity of injury Presence of comorbidity Age Lung developmental period Potential for toxicity

Yes Yes Yes Yes Simple Short No Limited Limited No Young adult 2 weeks Limited

Yes Yes Yes Yes Complex Lifetime Yes Extensive Extensive Frequent Elderly Many years Extensive

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measuring the disease and monitoring its response to therapy. Comorbid conditions are also common in patients with emphysema, including chronic bronchitis and bullous lung disease, as well as precancerous changes, heart disease, and other chronic medical conditions (21). Medications that are tolerated for the short term in animals may produce considerable side effects when used to treat this population of patients for extended periods of time. Interspecies and age-related differences in gene regulation also likely exist, as well as considerable differences in the normal rate of lung maturation and the duration of disease (22,23). Therefore, although animal models provide essential information and a strong motivation to treat patients, understanding the capacity for retinoids to stimulate repair in the mature human lung will require carefully designed and well-controlled human clinical trials. This chapter reviews the rationale for using retinoids to treat human emphysema, describes a strategy for investigating their therapeutic use, and summarizes results from early clinical investigations. II. Using Retinoids to Treat Emphysema Retinoids constitute a group of pleotropic regulatory molecules that mediate their effects by binding to heterodimeric receptor complexes composed of retinoic acid receptors (RAR), retinoid X receptors (RXR), and a variety of other steroidlike receptor proteins including vitamin D, estrogen, and thyroid receptors (24). Under physiologic conditions, retinoids are probably derived from intracellular oxidation of plasma retinol and carptenes (such as h-carotene) absorbed from the gastrointestinal GI tract (25). Intracellular isomerases further convert these compounds into their biologically active forms including 9-cis-, 11-cis-, or 13-cis-retinoid acid (26,27). Each cell type seems to produce its own pool of retinoids, which normally function as what are termed intracrine or paracrine mediators. With respect to the lung, the accumulation of retinoids, and activation of their receptors, leads to transcriptional regulation of genes involved in epithelial cell proliferation, differentiation, and morphogenesis (28,29); elaboration of matrix proteins including collagen and elastin (30,31); production and balance of both proteases and antiproteases (32–34); inflammatory cell activation (35); cytokine and chemokine production (35–37); and secretion of mucus and surfactant (38–40). All of these tissues, cells, and processes are altered in the emphysematous lung, providing a biological rationale for considering retinoids as a potential therapy. Developmental studies, focusing on postnatal lung development, document that both endogenous and exogenous retinoids can regulate these events in a coordinated manner to produce functional alveolar gas-exchange units (17). There is a clear temporal and spatial

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accumulation of retinoids, retinoid-binding proteins, and retinoic acid receptors in the developing lung during the time of maximal alveolar septation (15,16,22). Administration of exogenous retinoic acid to newborn rats promotes development in the lungs of a larger number of smaller, more efficient alveoli and overcomes the suppressive effects that glucocorticoids have on septation and alveolar maturation (17). More recently, the use of specific RAR and/or RXR knockout mice has demonstrated that activation of some retinoid receptors, namely RARh, can inhibit alveolarization, while activation of other receptors, such as RARg, promote it (41,42). Although the coordinated regulation of lung growth by retinoids is well documented for the developing lung, recent work by Massaro and Massaro (13) suggested for the first time that administration of exogenous retinoids can recapitulate these events in the mature, but damaged, lung.

III. Clinical Availability and Experience An important factor in considering retinoids as a treatment for human emphysema is their track record in treating other medical problems. Retinoids have been used to treat a variety of human diseases ranging from dermatological disorders to malignancies. Perhaps the best examples of this are the Food and Drug Administration’s (FDA) approved treatments using 13-cis retinoic acid (cRA) for acne (43,44) and ATRA for acute promyelocytic leukemia (45,46) (Table 2). There is also considerable evidence suggesting that retinoids may have a role as chemotherapeutic or chemopreventive agents for

Table 2 Retinoids Approved for Human Use FDA-approved indications

Recommended dosages

Duration of treatment

13-cis retinoic acid (isotretinoin)

Severe recalcitrant nodular acne

Maximum 15–20 weeks, may be repeated after 2 months

Stable, first-order kinetics

All-trans retinoic acid (tretinoin)

Induction therapy for acute promyelocytic leukemia

0.5–2.0 mg/kg/day in divided doses twice daily 45 mg/m2/day in divided doses twice daily

Maximum 90 days

Induces own metabolism with levels reduced by 2/3 after 1 week

Metabolism

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malignancy. Multiple phase I and phase II trials with both ATRA and cRA have evaluated their efficacy in a variety of malignant or premalignant states, as well as their safety profile and pharmacokinetics (47–54). In general, side effects produced by the clinical use of ATRA and cRA are frequent, but generally mild in degree and manageable (Table 3). The most frequently reported adverse events are similar to those resulting from high dosages of vitamin A (55). Headache occurring several hours after ingestion of the drug is very common (52,56). Mild analgesics generally suffice for control, and tolerance develops with continued use. Pseudotumor cerebri is a very rare complication to be considered in the setting of persistent or very severe headaches. Dry skin, itching, flaking, xerostomia, and cheilitis are also common, occurring in most treated patients. These reactions of skin and mucous membranes can be managed with topical lubricants or adjustments in dosing and rarely require interruption of drug therapy. Nasal stuffiness, clogged ears, and cervical or tonsillar lymphadenopathy have also been encountered. Fatigue, bone pain, and arthralgia may occur in 20–30 % of patients. Like headache, these effects tend to occur early during treatment and remit with continued therapy. Significant hypertriglyceridemia and hypercholesterolemia also occur, with hyperlipidemia being one of the dosage-limiting toxicities (47,53). Adverse consequences of this hyperlipidemia have not yet been described, but using these agent long-term in elderly patients at risk for diabetes and heart disease could increase the clinical importance of this side effect. Transient increases in levels of serum aminotransferases, alkaline phosphatase, and bilirubin have also been recorded in patients using retinoids, but permanent liver damage has not been reported (53). As a group, the retinoids are exceptionally potent teratogens that lead to marked craniofacial and limb deformities (57). Their use must be actively avoided in women likely to become pregnant. There is also concern regarding the administration of retinoids to individuals at risk for lung cancer if they continue to smoke. Several studies have indicated that active smokers treated with retinoids, including hcarotene and cRA, experience a higher incidence of new lung cancers than do placebo-treated controls (50,58). Perhaps the most pronounced toxicity

Table 3 Common Side Effects Associated with cRA and ATRA Therapy . . . . . .

Skin rash, drying, pruritius Xerostomia, cheilitis, mucositis Headache Hypertriglyceridemia Fatigue Bone pain, arthralgia

. . . . . .

Nausea, abdominal pain Liver function abnormalities Hypercholesterolemia Visual disturbances Reports of depression Category D teratogen

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associated with the clinical use of ATRA has been the acute promyelocytic leukemia (APL)–retinoic acid syndrome (59). This potentially life threatening complication results in respiratory insufficiency and acute respiratory distress syndrome (ARDS), and is characterized by fever, dyspnea, weight gain, pulmonary infiltrates, pleural effusion, and/or pericardial effusion. This syndrome has occasionally been accompanied by impaired myocardial contractility, episodic hypotension, and multiorgan failure. Cotreatment with corticosteroids reduces the incidence considerably. The pathogenesis of this complication is specific for acute promyelocytic leukemia and is likely related to toxic degranulation by responding leukemic cells. Although both ATRA and cRA can cause minor leukocytosis or increases in red cell mass in any patient, the APL–retinoic acid syndrome occurs exclusively in patients with leukemia and should not be an issue when used for other indications. Of more potential importance to patients with emphysema is that retinoids have been associated with depression and bronchospasm (60,61). However, the relationship of these complications to drug administration is unclear and their applicability to elderly patients with emphysema is currently unknown. A wealth of knowledge exists regarding the potential complications of retinoids, their pharmacokinetics, and the dosages that can be safely given for sustained periods of time. This information provides a rationale for selecting specific retinoid dosages, for screening patients for risk factors, and monitoring their responses to avoid toxicity.

IV. Evaluating Different Retinoic Acid Derivatives Both 13-cis retinoic acid and ATRA are approved by the FDA for clinical use and are commercially available, which facilitates their evaluation in earlystage trials for emphysema. cRA is a biologically active isomer of ATRA: up to 30% of orally administered cRA spontaneously isomerizes to ATRA (62). There are several reasons to consider it as an alternative agent to ATRA. Although cRA shares many of the biological effects of ATRA, its clinical pharmacology is very different. ATRA is more rapidly cleared from plasma following oral administration, reducing its bioavailability. ATRA also autoinduces its own oxidative catabolism by hepatic P450 enzymes, resulting in progressively declining levels when administered continuously over time (63,64). Plasma concentrations of ATRA decrease by an average of 60– 70% when given continuously for even one week (Table 2). This may be clinically significant when given long-term to patients and may be responsible for what is termed the retinoic acid resistance syndrome associated with clinical relapses in patients treated for acute promyelocytic leukemia (63). This autoinduction of metabolizing enzymes does not occur with cRA, which

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is a potentially important difference. In addition to pharmacokinetic advantages, cRA is also more readily available (marketed as Accutane). Both retinoids are known to exert their effects via retinoid receptors, although they interact with different affinities to the various receptor subtypes (65). It is interesting that pretreatment with cRA was reported to convert an ATRAunresponsive cancer cell line to an ATRA-responsive one by upregulating expression of retinoic acid receptors. Thus, treating with cRA may potentiate the effects of other retinoids, including ATRA (66). These favorable characteristics support the choice of cRA as an alternative retinoid to evaluate for the treatment of emphysema. cRA and ATRA are both considered nonselective retinoids, binding to all three major RAR subtypes: a, h, and g. Studies with selective agonists and antagonists, or in receptor subtype knockout mice, suggest that simultaneous activation of RARh and RARg might limit alveolar formation compared to stimulation of RARg alone (41,42). RARg is also preferentially expressed in skin and lung, while RARh is preferentially expressed in liver, suggesting that receptor-selective ligands might have advantages in limiting toxicity (67). Activation of RXR receptors may also play a role in lung morphogenesis, as demonstrated in both knockout mice (42) and in rodent models evaluating the utility of 9-cis retinoic acid, a RXR-selective retinoid, in promoting alveolar reconstitution in elastase-treated rats (14). As information is gained from in vitro studies now underway and from animal models, and experience is gained from initial clinical investigations with cRA and ATRA, custom-designed retinoids with different patterns of receptor selectivity may become increasingly attractive as potential therapeutic agents. There is also considerable interest in inhaled retinoids for delivering high local drug concentrations while limiting their systemic effects (68–70). Animal models have already demonstrated the potential feasibility of this approach as chemoprevention for lung cancer (68). However, there are still obstacles to be overcome including the ability to deliver medication selectively to alveolar tissue, while limiting exposure in the oropharynx and conducting airways. Bronchospasm, epithelial changes, and mucus hypersecretion are all potential consequences of airway delivery that may pose problems in the treatment of patients with chronic obstructive pulmonary disease (38,60,71). Advances in ultrafine particle preparations, currently being tested for the delivery of inhaled corticosteroids, may overcome some of these concerns. Retinoids are also extremely teratogenic, leading to speculation that bystanders might be exposed to higher than acceptable secondary exposure to inhaled medications. Again, as with receptor-selective retinoids, there is a clear rationale for initial human studies to focus on previously tested compounds with easily controlled routes of delivery. Once potential treatment obstacles

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are identified and benefits defined, there will likely be indications to evaluate alternative preparations and routes of delivery.

V. Early-Phase Clinical Trials: Inclusion and Exclusion Criteria Early-phase studies require a significant focus on safety and tolerability. It is therefore necessary to establish eligibility criteria that will minimize potential adverse events and facilitate completion of clinical trials. At the same time, in order to document a benefit, the extent of disease needs to be accurately measured and reproducibly evaluated over time. Patients’ age, comorbid conditions, disease type and severity, and potential risk for drug toxicity all need to be carefully considered when one is establishing inclusion and exclusion criteria. Symptomatic emphysema is a disease of the elderly, rarely occurring before the age of 50 and with the majority of patients greater than 65 years old (72). Even in individuals with alpha-1-antitrypsin deficiency, the majority of symptomatic patients are still over age 50 (73). Establishing a lower age limit of 45–50 would therefore encompass the majority of eligible patients while reducing the medication-associated risk to individuals of reproductive potential. However, women less than 5 years postmenopausal should be enrolled only after reproductive counseling and implementation of effective birth control. Primary inclusion criteria should focus on validated measures for identifying emphysema (Table 4). In the majority of patients, emphysema coexists to variable degrees with chronic bronchitis, small airways disease, and reactive airways disease (6,7). These concurrent conditions affect symptoms, alter measured pulmonary function, and may lead to therapy-associated side effects, but are not expected to respond to retinoids. Although spirometry is the most widely used tool for diagnosing and measuring chronic obstructive pulmonary disease (COPD) (8), it does not focus on the destruction of alveolar septa and the enlargement of terminal airspaces, which are the hallmarks of emphysema (5). A moderate obstructive pattern on spirometry [forced expiratory volume in 1s (FEV1)