Lung Injury: Mechanisms, Pathophysiology, and Therapy

LUNG INJURY

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. Dlagnostic 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 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. Pathophyslology and Treatment of Inhalation Injuries, edited by J.Loke

35. Resplratory 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.Scharfand 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 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 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 Genetlcs 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. Parasitlc 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 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 Upperand 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. Multlmodality 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. Dlagnostic Pulmonary Pathology, edited by P.T.Cagle 143. Particle-Lung Interactions, edited by R.Gehrand 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 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-lgE Therapy in Asthma and Allergic Disease, edited by R.B.Flck, 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.R.Maurer 177. Therapeutic Targets in Airway Inflammation, edited by N.T.Eissa and D.P.Huston 178. Respiratory Infectlons 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 lll 186. Pleural Disease, edited by D.Bouros 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 191. Long-Term Intervention in Chronic Obstructive Pulmonary Disease, edited by R.Pauwels, D.S.Postma, and S.T.Weiss 192. Sleep Deprivation: Basic Science, Physiology, and Behavior, edited by Clete A.Kushida 193. Sleep Deprivation: Clinical Issues, Pharmacology, and Sleep Loss Effects, edited by Clete A.Kushida 194. Pneumocystis Pneumonia: Third Edition, Revised and Expanded, edited by P.D.Walzer and M.Cushion 195. Asthma Prevention, edited by William W.Busse and Robert F.Lemanske, Jr. 196. Lung Injury: Mechanisms, Pathophysiology, and Therapy, edited by Robert H.Notter, Jacob N.Finkelstein, and Bruce A.Holm The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.

LUNG INJURY Mechanisms, Pathophysiology, and Therapy Edited by

Senior Editor Robert H.Notter University of Rochester Rochester, New York, U.S.A. Jacob N.Finkelstein University of Rochester Rochester, New York, U.S.A. Bruce A.Holm State University of New York at Buffalo Buffalo, New York, U.S.A.

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Introduction Lung injury is a very broad clinical entity that may result from both endogeneous and exogeneous factors. Much credit must be given to Ashbaugh et al. who introduced the term Acute Respiratory Distress Syndrome (ARDS) in 1967.* Initially, this condition was defined by the widespread pulmonary infiltrate seen on chest X-rays, hypoxia and poor pulmonary compliance. Clinicians and health officials soon discovered the high prevalence and mortality of this condition resulting from a multifaceted etiology. Over the last 30 years, a large number of studies have been conducted to attempt to uncover the pathogenesis of ARDS and to develop effective treatments. From this very intense work, the extreme complexity of this syndrome became apparent, but it was also discovered that many of the pathogenic pathways relevant to ARDS were also features, albeit with variations, of other conditions resulting either from an acute lung injury like ARDS or from a chronic disorder such as pulmonary fibrosis. Thus, the term “lung injury” became preferred to explain the similarity of the cellular and subcellular manifestations resulting from pathologies of different origin. This volume titled Lung Injury: Mechanisms, Pathophysiology, and Therapy and edited by Drs. Robert H.Notter, Jacob N.Finkelstein, and *

Ashbaugh DG, Bigelow DP, Petty TL and Levine BE. Acute respiratory disease in adults. Lancet. 1967; 2:320–323.

Bruce A.Holm gives the reader a panoramic—indeed, unique—description of lung injury. Most volumes addressing lung injury focus almost exclusively on one cause of lung injury. This monograph presents the most current knowledge of the mechanisms of lung injury as well as therapeutic options which are derived from the mechanistic determinants. Its very valuable feature is the construct of each chapter, which leads the reader to a set of research questions that hopefully will stimulate both researchers and clinicians. Since its inception, the series of monographs Lung Biology in Health and Disease has included several volumes on diseases causing lung injury. In a way, this new volume is an “integration” of all the previous monographs. Undoubtedly, readers will be challenged. I deeply appreciate the work of the editors and authors to develop this monograph and I am grateful to them for the opportunity to include it in the series. Claude Leufant, M.D. Gaithersburg, Maryland

Preface This book attempts the challenging task of providing an integrated synopsis of basic concepts, topical review, and clinical therapies relevant for pulmonary inflammation and acute and chronic lung injury. Individual chapters have been written separately, but the authors and editors have made a conscious effort to integrate coverage and emphasize connections between different areas of lung injury research and applied therapeutics. Coverage in each chapter typically proceeds from general principles and concepts to specific discussion and review of current research perspectives. The direct complementarity between mechanistic. basic science understanding and clinical therapies is a major area of focus. In particular, current and evolving treatments for clinical lung injury in the latter part of the book are presented in the context of basic science understanding and research perspectives developed in preceding chapters. The editors and chapter authors hope very much that the book will prove useful to a broad audience of basic biomedical researchers and physician-scientists working in pulmonary biology, toxicology, and pulmonology, as well as to physicians-in-training and graduate students interested in learning about lung injury and its important clinical consequences. Robert H.Notter Jacob N.Finkelstein Bruce A.Holm

Contributors Tiina M.Asikainen Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland, and National Jewish Medical and Research Center, Denver, Colorado, U.S.A. William S.Beckett Departments of Medicine and Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, New York, U.S.A. John A.Belperio Department of Medicine, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, California, U.S.A. Peter B.Bitterman Department of Medicine, University of Minnesota, School of Medicine, Minneapolis, Minnesota, U.S.A. Stephen M.Black Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, Montana, U.S.A. Mahesh Bommaraju Department of Pediatrics, State University of New York (SUNY) at Buffalo, The Women & Children’s Hospital of Buffalo, Buffalo, New York, U.S.A. Arnold R.Brody Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, U.S.A. Patricia R.Chess Departments of Pediatrics and Environmental Medicine, University of Rochester, Rochester, New York, U.S.A. Ian Copland Department of Laboratory Medicine and Pathology, Lung Biology Research Programme, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada Daniel L.Costa Pulmonary Toxicology Branch, Experimental Toxicology Division, National Health and Environmental Research Laboratory, Research Triangle Park, North Carolina, U.S.A. Carl T.D’Angio Department of Pediatrics and Environmental Medicine, University of Rochester School of Medicine, Rochester, New York, U.S.A. Ian C.Davis Department of Anesthesiology, University of Alabamaat Birmingham, Birmingham, Alabama, U.S.A. C.C.Dos Santos Department of Critical Care Medicine, St. Michael’s Hospital and Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, Ontario, Canada Jeffrey R.Fineman Department of Pediatrics and Cardiovascular Research Institute, University of California, San Francisco, California, U.S.A. Jacob N.Finkelstein Departments of Pediatrics and Environmental Medicine, University of Rochester, Rochester, New York, U.S.A. J.Gauldie Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Adam Giangreco Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. M.Hitt Department of Oncology, Cross Cancer Institute, Edmondton, Alberta, Canada

Bruce A.Holm Departments of Pediatrics and Obstetrics and Gynecology, State University of New York (SUNY) at Buffalo, Buffalo, New York, U.S.A. Julia Kaufman Departments of Medicine and Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, New York, U.S.A. Michael P.Keane Department of Medicine, Division of Pulmonary and Critical Care Medicine, UCLA School of Medicine, Los Angeles, California, U.S.A. Paul R.Knight Departments of Anesthesiology and Microbiology, State University of New York (SUNY) at Buffalo, Buffalo, New York, U.S.A. M.Kolb Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada Vasanth H.Kumar Department of Pediatrics, State University of New York (SUNY) at Buffalo, The Women & Children’s Hospital of Buffalo, Buffalo, New York, U.S.A. Satyan Lakshminrusimha Department of Pediatrics, State University of New York (SUNY) at Buffalo, The Women & Children’s Hospital of Buffalo, Buffalo, New York, U.S.A. John D.Lang Department of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A. Joseph A.Lasky Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, U.S.A. Christine Martey Departments of Medicine and Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, New York, U.S.A. Sadis Matalon Departments of Anesthesiology, University of Alabama at Birmingham, Birmingham, Alabama, U.S.A. Frederick C.Morin, III Department of Pediatrics, State University of New York (SUNY) at Buffalo, The Women & Children’s Hospital of Buffalo, Buffalo, New York, U.S.A. Robert H.Notter Departments of Pediatrics and Environmental Medicine, University of Rochester, Rochester, New York, U.S.A. Michael A.O’Reilly Departments of Pediatrics and Environmental Medicine, University of Rochester, Rochester, New York, U.S.A. Luis A.Ortiz Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. David Perlman Department of Medicine, University of Minnesota, School of Medicine, Minneapolis, Minnesota, U.S.A. Richard Phipps Departments of Medicine and Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, New York, U.S.A. Martin Post Departments of Pediatrics, Physiology, and Laboratory Medicine and Pathology, Lung Biology Research Programme, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada Gloria S.Pryhuber Departments of Pediatrics and Environmental Medicine, University of Rochester School of Medicine, Rochester, New York, U.S.A. Susan D.Reynolds Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.

Alexandre T.Rotta Department of Anesthesiology, State University of NewYork (SUNY) at Buffalo, Buffalo, New York, U.S.A. Rita M.Ryan Department of Pediatrics, State University of New York (SUNY) at Buffalo, The Women & Children’s Hospital of Buffalo, Buffalo, New York, U.S.A. P.J.Sime Departments of Medicine and Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, New York, U.S.A. A.S.Slutsky Department of Critical Care Medicine, St. Michael’s Hospital and Interdepartmental Division of Critical Care, Department of Medicine, University of Toronto, Toronto, Ontario, Canada Robert M.Strieter Department of Pathology and Laboratory Medicine, UCLA School of Medicine, Los Angeles, California, U.S.A. Barry R.Stripp Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A. Keith Tanswell Departments of Pediatrics and Physiology, Lung Biology Research Programme, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada Thomas H.Thatcher Departments of Medicine and Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine, Rochester, New York, U.S.A. Zhengdong Wang Department of Pediatrics, University of Rochester, Rochester, New York, U.S.A. Stephen Wedgwood Department of Pediatrics, Northwestern University Medical School, Chicago, Illinois, U.S.A. Christine H.Wendt Department of Medicine, University of Minnesota, School of Medicine, Minneapolis, Minnesota, U.S.A. Carl W.White National Jewish Medical and Research Center, Denver, Colorado, U.S.A. R.J.White Department of Medicine (Division of Pulmonary and Critical Care Medicine), University of Rochester School of Medicine, Rochester, New York, U.S.A.

Contents Introduction Claude Lenfant

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Preface

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Contributors 1. Introduction to Lung Injury Robert H.Notter, Jacob N.Finkelstein, and Bruce A.Holm 2. Principles of Lung Development, Growth, and Repair Ian Copland, Keith Tanswell, and Martin Post 3. Acute Lung Injury: Etiologies and Basic Features Paul R.Knight and Alexandre T.Rotta 4. Mediators and Inflammatory Cell Recruitment in Acute Lung Injury Michael P.Keane, John A.Belperio, and Robert M.Strieter 5. Chronic Lung Injury: Basic Features and Clinical Relevance David Perlman, Peter B.Bitterman, and Christine H.Wendt 6. Mediators and Mechanisms in Chronic Lung Injury and Fibrosis Joseph A.Lasky, Luis A.Ortiz, and Arnold R.Brody 7. Roles of Reactive Oxygen and Nitrogen Species in Lung Injury Ian C.Davis, John D.Lang, and Sadis Matalon 8. Vascular Dysfunction in Lung Injury Stephen Wedgewood, Jeffrey R.Fineman, and Stephen M.Black 9. Surfactant Activity and Dysfunction in Lung Injury Zhengdong Wang, Bruce A.Holm, Sadis Matalon, and Robert H.Notter 10. Cell and Animal Models of Lung Injury Jacob N.Finkelstein, Michael A.O’Reilly, Bruce A.Holm, Patricia R.Chess, and Robert H.Notter 11. Genetically Modified Mouse Models of Lung Injury and Repair Barry R.Stripp, Adam Giangreco, and Susan D.Reynolds 12. Inhalation Toxicology: Methods and Models Daniel L.Costa 13. Ventilation Therapies and Strategies for Acute Lung Injury C.C.Dos Santos and A.S.Slutsky 14. Anti-inflammatory Therapies for Lung Injury Richard Phipps, William S.Beckett, Julia Kaufman, Christine Martey, P.J.Sime, and Thomas H.Thatcher 15. Surfactant Replacement Therapy in Lung Injury Patricia R.Chess, Jacob N.Finkelstein, Bruce A.Holm, and Robert H.Notter

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1 15 54 92 125 145 193 230 253 307

349 404 449 500

537

16. Antioxidant Therapy for Lung Injury Tiina M.Asikainen and Carl W.White 17. Vascular Therapies in Lung Injury Mahesh Bommaraju, Vasanth H.Kumar, Satyan Lakshminrusimha, Rita M.Ryan, and Frederick C.Morin, III 18. Gene Therapy for Lung Injury P.J.Sime, M.Kolb, R.J.White, M.Hitt, and J.Gauldie 19. Combination Therapies for Lung Injury Gloria S.Pryhuber, Carl T.D’Angio, Jacob N.Finkelstein, and Robert H.Notter 20. Summary and Future Research Directions Robert H.Notter, Jacob N.Finkelstein, and Bruce A.Holm Index

582 615

653 680

729 738

1 Introduction to Lung Injury ROBERT H.NOTTER, JACOB N.FINKELSTEIN, and BRUCE A.HOLM Departments of Pediatrics and Environmental Medicine, University of Rochester, Rochester, New York, U.S.A., and Departments of Pediatrics and Obstetrics and Gynecology, State University of New York (SUNY) at Buffalo, Buffalo, New York, U.S.A.

I. Overview To physicians and basic biomedical scientists, the term “injury” implies more than simply cuts, abrasions, fractures, or other readily apparent forms of trauma. Rather, injury is used in a broader context to denote damage to organs, cells, and tissues at the molecular, biochemical, or physiological level. One of the most widely studied areas in pulmonary biology over the past several decades involves lung injury and the fundamental mechanisms that contribute to it. The structural and functional integrity of the pulmonary vasculature, alveoli, airways, and interstitium are essential for life. This book addresses the mechanistic pathophysiology of acute and chronic lung injury, including both basic concepts and current research perspectives. Also emphasized is the translation of emerging basic science understanding to improve the range and effectiveness of clinical therapies for injury-related pulmonary diseases in infants, children, and adults. The pulmonary system is particularly sensitive to injury. The lungs are directly and continuously exposed to the environment via the airways, and face a spectrum of potential inhalation hazards from which other organs are shielded. The pulmonary alveoli and airways in mammals comprise a surface area of approximately 1 m2 per kilogram of body weight that is at risk for injury or alteration from external agents. The broad extent and fragile nature of the pulmonary capillary network similarly makes the lungs sensitive to injury from the vascular side. With each systolic contraction of the heart, the lungs receive a volumetric blood flow equal to that of the remainder of the body. This blood flow is distributed through a vascular network with a huge capillary cross-sectional area, which facilitates gas exchange and broadly distributes nutrients within the lungs. However, the extensive pulmonary microcirculatory blood flow can have detrimental consequences if it carries substances that are toxic or injurious. The thin-walled pulmonary capillaries are sensitive to permeability damage and high-molecular-weight edema is common in many forms of acute lung injury. Clinically important respiratory deficits arise from any process or combination of processes that compromise a significant portion of the pulmonary vasculature, airways, or alveoli. Thus, acute and chronic lung injury are frequent contributors to pulmonary disease in infants, children, and adults.

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Injury to the lungs interacts with ongoing growth and development. Like the majority of organs, the lungs continue to develop and grow postnatally as well as prenatally. Many of the cellular and molecular processes and pathways active in normal lung development and growth are recapitulated during injury and repair. In the absence of injury, or with effective repair, the lungs are a highly efficient organ system for gas exchange. However, if inflammatory lung injury is severe or progressive, or if repair of injury is abnormally regulated so that normal growth and development are compromised, serious consequences to the organism occur. The regulation and interaction of growth, development, inflammation, and repair are highly active areas of current pulmonary research. The proper balance of these processes is necessary for normally functioning lungs with adequate host defense capabilities. How the lungs accomplish this, or fail to do so, in response to various injury stresses is a major focus of this book.

II. Acute Lung Injury Lung injury occurs through a cascade of processes beginning with an acute insult and an associated acute innate inflammatory response. Acute pulmonary injury then either resolves or progresses to persistent chronic pathology involving abnormal remodeling and tissue repair.aThe pathophya

The terms “acute” and “chronic” are qualitative only. Acute lung injury commonly occurs over timescales of minutes to days following exposure to an initiating agent or condition, while chronic lung injury may involve pathology persisting for weeks to years depending on the specific injury stimulus and the animal species.

siology of acute inflammatory lung injury is complex in its features, mechanisms, and regulation. The lungs contain a large number of functionally specific cell types that can potentially be affected during injury, as well as an extensive interstitial matrix to support the airways, alveoli, and vasculature. Table 1 notes some of the many pathological features and processes that may be associated with acute pulmonary injury. One common aspect of the pathology of acute lung injury is damage to the cells of the alveolocapillary membrane (type I and type II alveolar epithelial cells and capillary endothelial cells) with a loss of barrier integrity. If endothelial permeability alone is increased, the resultant high-molecular-weight edema may be confined to the interstitium. However, if epithelial permeability is also compromised, edema can be distributed throughout the alveoli and interstitium even if lymphatics remain functional. Another important pathophysiological feature of acute lung injury is inflammation. The innate pulmonary inflammatory response is complex, involving the recruitment and activation of circulating leukocytes as well as participation by resident lung cells. Moreover, an almost bewildering number of inflammatory mediators, factors, and transduction and regulatory pathways are involved in acute pulmonary inflammation and injury.b Examples of inflammatory mediators and factors relevant for acute lung injury are given in Table 2. Basic research described in the following chapters has provided important information on the activities and interactions of inflammatory mediators, and has allowed several helpful categorizations to be developed. Subgroups of cytokines can be viewed as having pro-inflammatory, antiinflammatory, or down-modulatory activity, or as

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appearing early or late in the inflammatory response. Also, chemotactic cytokines (chemokines) can be grouped in C, CC, and CXC families to help to correlate their cellular effects (Chapter 4). The activities and responses of cytokines can also be better understood by categorizing their production by specific cell types or subsets of cells. For example, CD4+ lymphocytes (T-helper cells), which play crucial roles in cell-mediated adaptive immune responses, can be divided into functional subsets as Th1 (T-helper-1) cells and Th2 (T-helper-2) cells that produce cytokines with diverse or opposing regulatory or cellular activities. Th1 cells secrete interleukin (IL)-2, interferon-γ (IFN-γ) and tumor necrosis factor α and β (TNFα, TNFβ), while Th2 cells secrete IL-4, IL-5, IL6, IL-9, IL-10, IL-13, and TNFα. Th1 type immune responses tend to be more important in intracellular host defense against viruses and microorganisms and in delayed hypersensitivity reactions including transplant rejection, while Th2 type immunity and secreted cytokines are more involved in antibody and allergic responses. Selected considerations b

For reviews of inflammatory mediators relevant for acute inflammatory lung injury see, for example, Refs. 1–13.

Table 1 Selected Aspects of the Complex Pathology of Acute Inflammatory Lung Injury Leukocyte recruitment and/oractivation Inflammatory mediators/factors produced Activation of resident pulmonary leukocytes Multiple mediators/factors produced by including alveolar and interstitial macrophages leukocytes, alveolar epithelial cells, airway cells, and interstitial cells Recruitment and activation of circulating Reactive oxygen/nitrogen species, proteases, neutrophils, macrophages, and lymphocytes phospholipases generated and antioxidants depleted Alveolar epithelial celldamage/alteration Microvascular dysfunction Alveolar type I cell injury and death Injury to capillary endothelial cells resulting in Alveolar type II cell injury and/orhyperplasia increased microvascular permeability Increased permeability of alveolar epithelial Interstitial and alveolar edema barrier Impaired surfactant synthesis, secretion, Perivascular inflammation recycling Abnormal nonsurfactant type II cell function Hypoxic vasoconstriction; ventilation/perfusion mismatching Lung surfactant dysfunction/inactivation Airway injury Biophysical inactivation by endogenous Injury to Clara cells, other airway epithelial cells inhibitors Chemical degradation by lytic enzymes, Injury to airway smooth muscle cells oxidants Altered alveolar surfactant aggregate subtypes Small airway inflammation, collapse, or spasm Pulmonary interstitial injury Coagulation abnormalities Less prominent in acute vs. chronic injury Disseminated intravascular coagulation Early inflammation-induced changes in Micro- and macropulmonary emboli fibroblasts

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Early changes in extracellular matrix Inhibition of fibrinolysis The multifaceted pathology of acute inflammatory lung injury typically occurs over a timescale of minutes to days following an initiating event. Severe acute pulmonary injury is associated with acute respiratory failure and ALI/ARDS as discussed in the text and detailed in subsequent chapters.

Table 2 Selected Mediators, Receptors, and Chemical Factors Important in Acute Inflammatory Lung Injury Cytokines/growth factors EGF G-CSF GM-CSF INF-γ IL-1β, 4, 9 (pro-inflammatory) IL-6, 10 (anti-inflammatory) KGF TGFα TGFβ TNFα VEGF

Chemotactic cytokines (chemokines) ENA-78 MIP-1 GRO RANTES IL-8, MIP-2 IP-10

Reactive oxygen/nitrogen species Free radicals Hydroxyl (•OH) Peroxyl (RO•2) Alkoxyl (RO•) Hydroperoxyl (HO•2) Superoxide (O•2−) Nitric oxide (NO•) Antioxidants Enzymes Catalase GSH peroxidases SODs

Nonradicals Peroxynitrite (ONO2⎯) Alkyl peroxynitrite (ROONO) Hydrogen peroxide (H2O2) Hydroperoxide (ROOH)

Nonenzymes Ascorbate GSH α-Tocopherol Uric acid

Membrane receptors/ligands/adhesion molecules CD14 (LPS receptor) CD40/CD40-ligand Glucocorticoid receptors β1-Integrins (e.g., αvβ1

LPS binding protein L-selectins (eg, CD62-L) VCAM-1, ICAM-1 β2–Integrins (e.g., CD11a, b/CD18)

MCP-1 Transcription factor families AP-1 (fos, jun) C/EBP (e.g., NF-IL-6) HSF IкB NFкB

Other mediators/compounds CBG HSPs CCSP Lactate Complement (and fragments) LPS Ecosinoids Neuropeptides Leukotrienes NOSs PGs (E, F, I families) PAF Thromboxanes PAF-AcH The tabulated mediators and factors are examples only. Inflammatory mediators important in acute lung injury are detailed further in Chapters 3 and 4. CBG: corticosteroid binding globulin; CCSP: clara cell secretory protein; C/EBP: cyclic AMP/enhancer binding protein; EGF: epidermal growth factor; ENA-78:epithelial cell-derived neutrophil activator 78; G-CSF: granulocyte-colony

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stimulating factor (CSF); GM-CSF: granulocyte macrophage-CSF; GRO: growth related oncogene; GSH: glutathione; HSF: heat shock transcription factor; HSPs: heat shock proteins; 1CAM-1: intercellular adhesion molecule-1; IFN: interferon; IL (interleukin); LPS: lipopolysaccharide; KGF: keratinocyte growth factor; MCP: monocyte chemoattractant protein; MIP: macrophage inflammatory chemokine; NF: nuclear factor; NOSs: nitric oxide synthetases; PAF: platelet activating factor; PAF-AcH: PAF-acetylhydrolase; PGs: prostaglandins; RANTES: regulated on activation normal Texpressed and secreted; SODs: superoxide dismutases; TGF: transforming growth factor; TNF: tumor necrosis factor; VCAM-1: vascular cell adhesion molecule-1; VEGF: vascular-endothelial growth factor. Source: Compiled by Notter (63) from Refs. 3,5–9,28,29,64–80.

Table 3 Considerations Involved in Assessing the Activities and Interactions of Individual Inflammatory Mediators During Lung Injury Biochemical characteristics Cytokine family membership (e.g., C, CC, CXC families of chemokines, etc) Primary cell receptor (s) or receptor family including specific binding behavior Species specificity (e.g., human vs. mouse differences in cytokine nomenclature, structure, etc.) Cell-specific production By resident pulmonary epithelial, endothelial, interstitial cells By resident pulmonary leukocytes vs. recruited leukocytes By specific subgroups of leukocytes (e.g., T-helper cells producing Th1 and Th2 cytokines) Timing and patterns of mediator production and release Biological distribution (e.g., local vs.systemic concentration; intracellular vs. extracellular concentration) Timing of production/release relative to other mediators (e.g., early vs.late) Level and timecourse of production/release in relation to other mediators Activity characteristics Overall category of activity (e.g., proinflammatory vs.anti-inflammatory or down-modulatory) Direct effects on primary target cells and tissues Indirect effects in modulating the expression/production/release of other mediators with diverse actions Signal transduction pathways involved in direct/indirect activities Although the subdivisions in the table are arbitrary and selected, they emphasize the multifaceted and interdependent nature of the pulmonary inflammatory response. The production and activities of individual inflammatory mediators not only need to be understood and characterized at the biochemical, cellular, and molecular levels as a function of time, but also must be viewed in terms of interactions with other mediators having additional effects on cells and tissues.

important in assessing the activities and interactions of inflammatory mediators in lung injury are summarized in Table 3. Acute tissue injury and inflammation contribute to the pathophysiology of a variety of pulmonary diseases. However, the medical consequences of acute pulmonary injury are frequently defined symptomatically as syndromes: clinical acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS) (Chapter 3). The syndromes of ALI/ARDS can occur in patients of all ages, and arise from multiple etiologies that cause direct or indirect lung injury including sepsis, gastric aspiration, pulmonary infection,

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hypovolemic shock, chest trauma, head injury, long-bone fractures, near-drowning, closed space burn injuries, smoke inhalation, radiation, hyperoxia, and many others (e.g., Refs. 1,14–20). Although multiorgan pathology is often present in ALI/ARDS, these syndromes are diagnosed by criteria relating to acute respiratory failure (1). By definition, all patients with ARDS also have ALI, which requires a less severe level of impairment of gas exchange (1). The incidence of ALI/ARDS has been variably reported to be 50,000–150,000 cases per year in the United States, with high associated mortality and morbidity (1,14,17,21–26). A recent analysis by Goss et al. (27) has estimated that the actual incidence of clinical ALI in the United States is even higher at 22–64 cases per 100,000 persons per year. In addition to involving severe acute respiratory failure, ALI/ARDS can also progress to a “fibroproliferative” phase of disease that involves chronic lung injury with tissue remodeling and the initiation of fibrosis (15,18–20).

III. Chronic Lung Injury Chronic injury is closely linked to abnormalities of tissue repair, i.e., the set of responses from cells intended to counteract and recover from trauma or other pathological alteration. Aberrant repair typically occurs in association with persistent inflammation and tissue damage, and is ultimately apparent as scarring or fibrosis. By necessity, chronic injury includes effects from cellular and subcellular processes initiated earlier during acute injury. On average, the more severe the acute injury, the higher the risk for persistent chronic injury. However, this correspondence is not exact. Some patients who develop severe chronic fibrogenic lung injury may have modest or minimal apparent levels of acute injury. Conversely, patients with substantial acute pulmonary injury do not always develop severe chronic injury. Mechanisms of chronic fibrogenic lung injury are detailed in later chapters and reviewed in Refs. 28–39. Selected features of chronic lung injury are summarized in Table 4. The pulmonary interstitium is generally prominently affected, and becomes thickened with increased numbers of fibroblasts and increased deposition of collagen and other connective tissue components. Chronic lung injury can also involve an early alveolitis, with activated macrophages, lymphocytes, neutrophils, or eosinophils causing inflammation-induced damage to the alveolar epithelium. Intra-alveolar fibrosis and thickening of the alveolar epithelial wall may also occur. A variety of mediators and factors produced by inflammatory leukocytes and pulmonary endothelial, epithelial, and interstitial cells are thought to participate in the development and progression of fibrogenic chronic lung injury (see Table 5 for selected examples). In addition to the mediators and factors in Table 5, many of those given earlier as being involved in acute pulmonary injury in Table 2 are also relevant for tissue remodeling, repair, and chronic injury. As in the case of acute injury, specific signaling pathways and regulatory processes important in chronic lung injury and repair are active current areas of research investigation.

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Table 4 Selected Aspects of the Pathology of Fibrogenic Chronic Lung Injury General connective tissue repair/remodeling Proliferation and migration of fibroblasts Microvascular regeneration and repair Deposition of extracellular matrix

Interstitial injury Damage to fibroblasts and other interstitial cells Production of abnormal collagen bundles, types Abnormal matrix production (e.g., fibronectin, laminin) Maturation/organization of fibrous tissue Abnormal new vessel formation (abnormal angiogenesis) Interstitial fibrosis and scarring Fibrosing alveolitis Alveolar epithelial injury/alteration Persistent alveolar and peri-alveolar inflammation Injury/death of alveolar type I epithelial cells Alveolar accumulation of inflammation-induced Proliferation/alteration of alveolar type II cells products Consolidation and fibrosis of intra-alveolar Thickening of alveolar epithelial wall material Re-epithelialization of intra-alveolar material Loss of functional gas exchange units Abnormal surfactant metabolism, recycling Chronic endothelial injury Fibrogenic airway injury Endothelial cell injury, alteration, or death Injury or altered number of bronchiolar epithelial cells Abnormal mediator production by endothelium Proliferation/depletion of other airway lining cells Fenestrated endothelium with increased Abnormal airway wall remodeling and peripermeability airway fibrosis Disrupted and thickened endothelial basement Reduced airway function membranes Chronic injury typically becomes apparent over a prolonged timescale (e.g., weeks to months) after an initiating event. Chronic lung injury often involves prominent elements of abnormal tissue remodeling and repair following a progressive acute inflammatory injury, but chronic fibrogenic pathology can also occur without substantial apparent acute inflammation and injury.

Table 5 Selected Factors and Enzymes Involved in Tissue Repair, Wound Healing, and Chronic Lung Injury Growth factors Fibroblast migration (e.g., PDGF, EGF, FGFs, TGFβ, TNFα) Fibroblast proliferation (e.g., PDGF, EGF, FGFs, TNFα) Angiogenesis (e.g., VEGFs, angioproteins, FGFs) Collagen synthesis and/or secretion (e.g., CTGF, PDGF, EGF,FGFs, TGFβ, TNFα) Matrbc-modifying enzyme families Metalloproteinases (e.g., gelatinases A,B) TIMP’s (e.g., TIMP1-4) Collagenases (e.g., collagenase-1) Selected additional compounds/factors

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Collagens Angiotensinogen/angiotensin II PGs (e.g., PGE2) Surfactant proteins (e.g., SP-A/D) Leukotrienes (e.g., B4)

Fibronectin Procoagulant TF PAI-1, PAI-2 Endothelin-1 Cell adhesion molecules (e.g., ICAMs, VCAMs) Many of the mediators, factors, and signaling molecules listed earlier as important in acute lung injury in Table 2 also play roles in chronic injury. Details on the pathophysiology of chronic lung injury and the mediators involved are given in Chapters 5 and 6. CTGF: connective tissue growth factor; EGF: epidermal growth factor; FGF: fibroblast growth factor; ICAMs: intercellular adhesion molecules; PAI: plasminogen activator inhibitor; PDGF: platelet-derived growth factor; PGs: prostaglandins; procoagulant TF: procoagulant tissue factor; TGF: transforming growth factor; TIMPs: tissue inhibitor of metalloproteinases; TNF: tumor necrosis factor; VCAMs: vascular cell adhesion molecules; VEGF: vascular-endothelial growth factor. Source: Factors compiled from Refs. 28–39.

A number of important clinical respiratory diseases involve chronic injury. One example of this is the fibroproliferative pathology of late phase ALI/ARDS, as noted earlier. The interstitial lung diseases, also called the restrictive lung diseases, are perhaps the most important clinical manifestations of fibrogenic lung injury (15,18–20). These diseases comprise a heterogeneous group including idiopathic pulmonary fibrosis (IPF), pneumoconiosis from environmental or occupational inhalation exposure, sarcoidosis, pulmonary manifestations of collagen vascular diseases (e.g., scleroderma, lupus erythematosus, dermatoid arthritis), fibrosis in association with radiation and hypersensitivity pneumonitis, drug-induced fibrosis, and a number of others. Although classed as interstitial diseases, many of these disorders also incorporate a fibrosing alveolitis or related intra-alveolar component of pathology. Chronic obstructive lung diseases like emphysema, chronic bronchitis and bronchiolitis, and bronchiectasis in association with cystic fibrosis or persistent pulmonary infection also have elements of chronic injury, but fibrosis is generally less prominent than in the interstitial lung diseases. Interstitial lung diseases vary significantly in the details of their pathology and clinical course, but all share characteristic signs and symptoms. Functionally, the lungs have decreased compliance (∆V/∆P) and require increased expansion pressures. Pulmonary function testing indicates near-proportional reductions in vital capacity (VC) and the fraction of expired volume in one second (FEV)1, leading to little change in the (FEV)1/VC ratio. Patients typically have dyspnea, which may progress to hypoxemia with a chronic need for supplemental oxygen. Chest radiographs may show a hazy “ground glass” appearance in early alveolitis, but later disease is typified by changes associated with interstitial thickening (15, 18–20). IPF is detailed in later chapters as an important example of chronic interstitial lung disease (also see Refs. 29,31–42, for review). Idiopathic pulmonary fibrosis has an incidence of approximately 7/100,000 in women and 10/100,000 in men, and primarily occurs in individuals over the age of 50 (31,34,40–42), Respiratory deficits are progressive, and the five year survival of patients with a firm diagnosis of IPF is only about 30% (36). Diseases involving chronic lung injury occur not only in adults, but also in infants and children. One important example of chronic lung disease in premature infants is

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bronchopulmonary dysplasia (BPD). This condition was first defined in 1967 by Northway et al. (43) as a requirement for supplemental oxygen at 28 days of life in premature infants treated with mechanical ventilation for hyaline membrane disease (the neonatal respiratory distress syndrome, RDS). Alternatives to the original definition have since been proposed as surfactant therapy and other medical advances have improved the survival of premature infants, and new patterns of neonatal chronic lung disease (CLD) have emerged. The majority of very premature infants with birth weights of 500–1000 g now survive, and a substantial percentage require some supplemental oxygen at 28 days of life. In many of these very premature infants, there is no clear connection between their chronic need for oxygen at 28 days and the incidence and severity of earlier acute RDS, indicating that developmental phenomena may be important in the underlying pathophysiology (44,45). A common current definition for BPD or CLD in premature infants is a requirement at 36 weeks corrected gestational age (postmenstrual age) for supplemental oxygen or ventilation either in the hospital or after discharge home (44,46). The incidence of BPD (CLD) in premature infants is inversely proportional to birth weight, but specific incidence numbers can vary significantly depending on patient demographics, diagnostic criteria, ventilation methods, and other variables (e.g., Refs. 44,45,47,48).

IV. Therapeutic Approaches for Diseases Involving Lung Injury The translation of basic research understanding to improve the clinical treatment of injury-related pulmonary diseases is an important focus of coverage in this book. The multifaceted pathophysiology of lung injury offers many potential therapeutic targets. Patients with injury-associated respiratory failure currently receive sophisticated mechanical respiratory support with a variety of different ventilator modalities (conventional, high-frequency oscillatory, or jet ventilation) and ventilation strategies to minimize ventilator-induced lung injury (Chapter 13). Antibiotics and antiviral agents are administered if underlying infection is present, and multiorgan failure is also addressed by specific therapies as needed. Additional therapeutic targets in the pathophysiology of clinical lung injury include inflammation, oxidant injury (Chapter 7), vascular dysfunction (Chapter 8), and surfactant dysfunction (Chapter 9). Examples of newer agents for mitigating inflammatory lung injury based on current scientific understanding include anti-inflammatory antibodies, receptors, and receptor antagonists; inhaled nitric oxide and other vasoactive drugs; exogenous surfactants; antioxidant agents; and potentially gene therapy agents (Chapters 14–19). Additional agents and interventions targeting specific aspects of acute and chronic lung injury are continuing to become available at a rapid rate through ongoing basic research on inflammation and lung injury and through new medical technology.*

V. Summary of Coverage and Chapter Organization Coverage in this book is designed to provide current research perspectives about lung injury and its therapy while also emphasizing basic conceptual principles. Each chapter

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begins with an Overview that outlines the topics and concepts covered, and ends with a Summary that recapitulates selected important scientific and conceptual points. Each also contains topical literature citations and review, integrated with material on fundamental concepts, principles, and mechanistic pathways. Discussion is augmented as much as possible with specific examples drawn from the literature. The material presented is by necessity selective, and exhaustive coverage of all biological and medical topics relevant for cell and tissue injury, growth, and development has not been attempted. In this sense, coverage here is *

Examples of review articles providing information on therapeutic agents and ventilation strategies for lung injury with or without associated sepsis include Refs. (3,9,10,12,13,17,30–32,39,49–62).

a stepping off point intended to be supplemented elsewhere based on individual priorities and interests. The initial third of the book focuses on the etiologies, pathophysiology, and mediators involved in acute and chronic lung injury. Chapter 2 covers general concepts of lung development and growth, which occur postnatally as well as prenatally and interact with lung injury and repair. Chapter 3 introduces basic concepts of acute pulmonary inflammation and related cells and mediators, with an emphasis on the mechanistic pathophysiology of clinical ALI and ARDS. Chapter 4 provides further coverage of important mediators involved in the acute innate pulmonary inflammatory response, particularly early response cytokines and families of chemokines that recruit and activate leukocytes. Chapters 5 and 6 provide analogous coverage on chronic lung injury, including its basic pathophysiology and clinical importance, plus selected mediators important in fibroproliferation and fibrosis. The middle third of the book begins with chapters on three important aspects of lung injury pathophysiology, i.e., reactive oxygen/nitrogen species, vascular dysfunction, and surfactant dysfunction. Chapter 7 discusses reactive oxygen and nitrogen species and their importance in lung injury, along with related pulmonary antioxidant defenses. Chapter 8 covers the pulmonary vasculature and the mechanisms that contribute to vascular dysfunction during lung injury. Chapter 9 covers pulmonary surfactant and its activity in normal and injured lungs, with an emphasis on mechanisms of surfactant dysfunction that contribute to ALI/ARDS and related respiratory failure. The next three chapters detail experimental models used in studying lung injury mechanisms and in developing and testing potential therapeutic agents and interventions. Chapter 10 gives an overview of cell and animal models in lung injury research, while Chapter 11 provides details on the highly important topic of genetically modified mouse models of lung injury and repair. In addition, Chapter 12 examines specific methods and animal models used in the important area of inhalation toxicology. The final third of the book focuses on current and future therapies for injury-related pulmonary diseases in the context of basic science understanding and perspectives in earlier chapters. Consistent with the multifaceted pathophysiology of acute and chronic lung injury, a spectrum of agents and interventions are relevant for treating these conditions. Chapter 13 covers ventilation therapies and strategies that form an essential component of therapy for all forms of respiratory failure. Chapter 14 examines agents targeting over-exuberant inflammation in the pathology of lung injury. Chapter 15

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discusses exogenous surfactants and their potential utility in the therapy of clinical ALI and ARDS in infants, children, and adults. Chapter 16 describes antioxidant therapies that target important oxidant-induced pathology during lung injury. Chapter 17 details vasoactive agents and their use in treating reactive vasoconstriction and other aspects of vascular dysfunction in injury-induced respiratory failure. Chapter 18 examines the topical area of gene-based interventions against lung disease and injury that may lead to important new clinical therapies in the future. Chapter 19 describes the rationale and utility of combination therapies for lung injury, where several agents or interventions are used concurrently to target multiple aspects of pathophysiology. This chapter also details important considerations that impact clinical trial evaluations of combination therapies for lung injury. Finally, Chapter 20 summarizes selected perspectives on on-going lung injury research, including the importance of newer approaches that integrate genomics, proteomics, bioinformatics, and systems biology in defining mechanisms and suggesting new therapeutic strategies. Continuing advances in mechanistic understanding about acute and chronic lung injury through basic research are essential for the future development of more optimal clinical therapies for a broad spectrum of injury-related respiratory diseases.

References 1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American–European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818–824. 2. Luce JM. Acute lung injury and the acute respiratory distress syndrome. Crit Care Med 1998; 26:369–376. 3. Karima R, Matsumoto S, Higashi H, Matsushima K. The molecular pathogenesis of endotoxin shock and organ failure. Mol Med Today 1999; 5:123–132. 4. Rinaldo JE, Rogers RM. Adult respiratory distress syndrome, changing concepts of lung injury and repair. N Engl J Med 1982; 15:900–909. 5. Meduri GU. The role of host defense response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment. Eur Respir J 1996; 9:2650–2670. 6. Chabot F, Mitchell JA, Gutteridge JMC, Evans TW. Reactive oxygen species in acute lung injury. Eur Respir J 1998; 11:745–757. 7. Hack CE, Aarden LA, Thijs LG. Role of cytokines in sepsis. Adv Immunol 1997; 66:101–195. 8. Sweet M, Hume D. Endotoxin signal transduction in macrophages. J Leukoc Biol 1996; 60:8–26. 9. Sessler C, Bloomfield G, Fowler A. Current concepts of sepsis and acute lung injury. Clin Chest Med 1996; 17:213–235. 10. Artigas A, Bernard GR, Carlet J, Dreyfuss D, Gattinoni L, Hudson L, Lamy M, Marini JJ, Matthay MA, Pinsky MR, Spragg R, Suter PM, and Consensus Committee.The AmericanEuropean consensus conference on ARDS, Part 2: ventilatory, pharmacologic, supportive therapy, study design strategies and issues related to recovery and remodeling. Intensive Care Med 1998; 24:378–398. 11. Hinshaw LB. Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med 1996; 24:1072–1078. 12. Temmesfeld-Wollbruck B, Walmrath D, Grimminger F, Seeger W. Prevention and therapy of the adult respiratory distress syndrome. Lung 1995; 173:139–164.

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13. Kollef MH, Schuster DP. The acute respiratory distress syndrome. N Engl J Med 1995; 332:27– 37. 14. Rubenfeld GD. Epidemiology of acute lung injury. Crit Care Med 2003; 31(suppl):S276–S284. 15. Cotran RS, Kumar V, Collins T. Robbins Pathologic Basis of Disease 6th ed. Philadelphia: W.B.Saunders, 1999. 16. Taussig LM, Landau LI, Le Souef PN, Morgan WJ, Martinez FD, Sly PDE. Pediatric Respiratory Medicine. St. Louis: Mosby,1999. 17. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334–1348. 18. Fishman AP, Elias JA, Fishman JA, Gripp M A, Kaiser LR, Senior RM. Fishman’s Pulmonary Diseases and Disorders. 3rd ed. New York: McGraw-Hill, 1998. 19. Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison’s Principles of Internal Medicine. 15th ed. New York: McGraw-Hill , 2001. 20. Murray JF, Nadel JA, Mason RJ, Boushey HA. Textbook of Respiratory Medicine 3rd ed. New York: W.B.Saunders, 2000. 21. Villar J, Slutsky AS. The incidence of the adult respiratory distress syndrome . Am Rev Respir Dis 1989; 140:814–816. 22. Hudson LD, Milberg JA, Anardi D, Maunder RJ.Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1995; 151:293–301. 23. Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome. JAMA 1995; 273:306–309. 24. Krafft P, Fridrich P, Pernerstorfer T, Fitzgerald RD, Koc D, Schneider B, Hammerle AF, Steltzer H. The acute respiratory distress syndrome; definitions, severity, and clinical outcome. An analysis of 101 clinical investigations. Intensive Care Med 1996; 22:519–529. 25. Hyers TM. Prediction of survival and mortality in patients with the adult respiratory distress syndrome. New Horizons 1993; 1:466–470. 26. Doyle RL, Szaflarski N, Modin GW, Wiener-Kronish JP, Matthay MA. Identification of patients with acute lung injury: predictors of mortality. Am J Respir Crit Care Med 1995; 152:1818–1824. 27. Goss CH, Brower RG, Hudson LD, Rubenfeld GD. ARDS Network. Incidence of acute lung injury in the United States. Crit Care Med 2003; 31: 1607–1611. 28. Zhang K, Phan SH. Cytokines and pulmonary fibrosis. Biol Signals 1996; 5: 232–239. 29. Ward PA, Hunninghake GW. Lung inflammation and fibrosis. Am J Respir Crit Care Med 1998; 157 (suppl):S123–S129. 30. Berthiaume Y, Lesur O, Dagenais A. Treatment of adult respiratory distress Syndrome: plea for rescue therapy of the alveolar epithelium. Thorax 1999; 54: 150–160. 31. Selman M, King TEJ, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134:136– 151. 32. American Thoracic Society, European Respiratory Society, and American College of Chest Physicians. Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. Am J Respir Crit Care Med 2000; 161:646–664. 33. Keogh BA, Crystal RG. Alveolitits: the key to the interstitial lung disorders. Thorax 1982; 37:1–10. 34. Crystal RG, Bitterman PB, Rennard SI, Hance AJ, Keogh BA. Interstitial lung diseases of unknown cause: disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 1984; 310:235–244. 35. Wolff G, Crystal RG. Biology of pulmonary fibrosis. In: Crystal RG, West JB, Weibel ER, Barnes PJ eds. The Lung: Scientific Foundations. 2nd ed. Philadelphia: Lippincott-Raven Publishers, 1997:2509–2524. 36. Strieter RM. Mechanisms of pulmonary fibrosis. Chest 2001; 120 (suppl): 77S–85S.

Introduction to lung injury

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37. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 1998; 157:1301–1315. 38. Finkelstein JN, Horowitz S, Sinkin RA, Ryan RM. Cellular and molecular responses to lung injury in relation to induction of tissue repair and fibrosis . Clin Perinatol 1992; 19:603–620. 39. Sime PJ, O’Reilly KMA. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol 2001; 99:308–319. 40. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung disease. Am J Respir Crit Care Med 1994; 150:967–972. 41. Mannino DM, Etzel RA, Parrish RG. Pulmonary fibrosis deaths in the United States,1979– 1991. An analysis of multiple-cause mortality data. Am J Respir Crit Care Med 1996; 153:1548–1552. 42. Schwartz DA, Helmers RA, Galvin JR, van Fossen DS, Frees KL, Dayton CS, et al. Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149:450–454. 43. Northway WHJ, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline membrane disease. N Engl J Med 1967; 276:357–368. 44. Hansen T, Corbet A. Chronic lung disease. In: Taeusch HW, Ballard RA eds. Avery’s Diseases of the Newborn. 7th ed. Philadelphia: W.B.Saunders Company, 1998:634–647. 45. Kotecha S, Silverman M. Chronic respiratory complications of prematurity. In: Taussig LM, Landau LI, eds. Pediatric Respiratory Medicine. St. Louis: C.V. Mosby, 1999:488–521. 46. Shennan AT, Dunn MS, Ohlsson A, Lennox K, Hoskins EM. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82:527–532. 47. Zimmerman JJ, Farrell PM. Advances and issues in bronchopulmonary dysplasia. Curr Prob Pediatr 1994; 24:159–170. 48. Bancalari E. Neonatal chronic lung disease. In:Fanaroff AA, Martin RJ, eds. Neonatal Perinatal Medicine. St. Louis: Mosby, 1997:1074–1089. 49. Hudson LD. New therapies for ARDS. Chest 1995; 108 (suppl):79S–91S. 50. Fulkerson WJ, Macintyre N, Stamler J, Crapo JD. Pathogenesis and treatment of the adult respiratory distress syndrome. Arch Intern Med 1996; 156:29–38. 51. Paulson T, Spear R, Peterson B. New concepts in the treatment of children with acute respiratory failure. J Pediatr 1995; 127:163–175. 52. Ring J, Stidham G. Novel therapies for acute respiratory failure. Pediatr Clin North Am 1994; 41:1325–1363. 53. Weikert LF, Bernard GR. Pharmacology of sepsis. Clin Chest Med 1996; 17: 289–305. 54. Thompson BT. Glucocorticoids and acute lung injury. Crit Care Med 2003; 31 (suppl):S253– S257. 55. Steinbrook R. How best to ventilate Trial design and patient safety in studies of the acute respiratory distress syndrome. N Engl J Med 2003; 348: 1393–1401. 56. Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acute hypoxemic respiratory failure in children and adults (update of Cochrane Database Syst Rev 2000; (4): CD002787; PMID: 11034763). Cochrane Database Syst Rev 2003; (1):CD002787. 57. Laterre PF, Wittebole X, Dhainaut JF. Anticoagulant therapy in acute lung injury. Crit Care Med 2003; 31 (suppl):S329–S336. 58. Lewis JF, Brackenbury A. Role of exogenous surfactant in acute lung injury. Crit Care Med 2003; 31 (suppl):S324–S328. 59. Kaisers U, Busch T, Deja M, Donaubauer B, Falke KJ. Selective pulmonary vasodilation in acute respiratory distress syndrome. Crit Care Med 2003; 31 (suppl):S337–S342. 60. Derdak S. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adult patients. Crit Care Med 2003; 31 (suppl):S317–S323. 61. Marraro G. Innovative practices of ventilatory support with pediatric patients. Pediatr Crit Care Med 2003; 4:8–20.

Lung injury

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62. Notter RH, Apostolakos M, Holm BA, Willson D, Wang Z, Finkelstein JN, Hyde RW. Surfactant therapy and its potential use with other agents in term infants, children and adults with acute lung injury. Perspectives Neonatol 2000; 1 (4):4–20. 63. Notter RH. Lung surfactants: Basic Science and Clinical Applications . New York: Marcel Dekker, 2000. 64. Nakos G, Kitsiouli EI, Tsangaris I, Lekka ME. Bronchoalveolar lavage fluid characteristics of early intermediate and late phases of ARDS. Intensive Care Med 1998; 24:296–303. 65. Meduri GU, Headley S, Tolley E, Shelby M, Stentz F, Postlewaite A. Plasma and BAL cytokine response to corticosteroid rescue treatment in late ARDS. Chest 1995; 108:1315–1325. 66. Headley AS, Tolley E, Meduri GU. Infections and the inflammatory response in acute respiratory distress syndrome. Chest 1997; 111:1306–1321. 67. Goodman, RB, Strieter RM, Martin DP, Steinberg KP, Milberg JA, Maunder RJ, Kunkel SL, Walz A, Hudson LD, Martin TR. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 154:602–611. 68. Baughman RP, Gunther KL, Rashkin MC, Keeton DA, Pattishall EN. Changes in the inflammatory response of the lung during acute respiratory distress syndrome: prognostic indicators. Am J Respir Crit Care Med 1996; 154:76–81. 69. Lucas R, Lou J, Morel DR, Ricou B, Suter PM, Grau GE. TNF receptors in the microvascular pathology of acute respiratory distress syndrome and cerebral malaria. J Leukoc Biol 1997; 61:551–558. 70. Chollet-Martin S, Jourdain B, Gribert C, Elbim C, Chastre J, Gougerot-Pocidalo MA. Interactions between neutrophils and cytokines in blood and alveolar spaces during ARDS. Am J Respir Crit Care Med 1996; 153:594–601. 71. Armstrong L, Millar AB. Relative production of tumour necrosis factor α and interleukin 10 in adult respiratory distress syndrome. Thorax 1997; 52: 442–446. 72. Parsons P, Gillesis M, Moore E, Moore F, Worthen G. Neutrophil response to endotoxin in the adult respiratory distress syndrome: role of CD14. Am J Respir Cell Mol Biol 1995; 13:152– 160. 73. Douzinas EE, Tsidemiadou PD, Pitaridis MT, Andrianakis I, Bobota-Chloraki A, Katsouyanni K, Sfyras D, Malagari K, Roussos C. The regional production of cytokines and lactate in sepsisrelated multiple organ failure. Am J Respir Crit Care Med 1997; 155:53–59. 74. Matute-Bello G, Liles WC, Radella F. Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med 1997; 156: 1969–1977. 75. Goodman ER, Kleinstein E, Fusco AM, Quinlan DP, Lavery R, Livingstone DH, Deitch EA, Hauser CJ. Role of interleukin 8 in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis. Arch Surg 1998; 13:1234–1239. 76. Pugin J, Ricou B, Steinberg KP, Suter PM, Martin TR. Proinflammatory activity in bronchoalveolar lavage fluids from patients with ARDS, a prominent role for interleukin–1. Am J Respir Crit Care Med 1996; 153:1850–1856. 77. Sempowski G, Chess P, Phipps R. CD40 is a functional activation antigen and B7-independent T cell costimulatory molecule in normal human lung fibroblasts. J Immunol 1997; 158:4670– 4677. 78. Adawi A, Zhang Y, Baggs R, Finkelstein J, Phipps R. Disruption of the CD40-CD40 ligand system prevents an oxygen-induced respiratory distress syndrome. Am J Pathol 1998; 152:651– 657. 79. Jorens PG, Sibille Y, Goulding NJ, van Overveld FJ, Herman AG, Bossaert L , DeBacker WA, Lauwerys R, Flower RJ, Bernard A. Potential role of Clara cell protein, and endogenous phospholipase A2 inhibitor, in acute lung injury. Eur Respir J 1995; 8:1643–1653. 80. Charafeddine L, D’Angio CT, Richards JL, Stripp BR, Finkelstein JN, Orlowski CC, LoMonaco MB, Paxhia A, Ryan RM. Hyperoxia increases keratinocyte growth factor mRNA expression in neonatal rabbit lung. Am J Physiol 1999; 20:L105–L113.

2 Principles of Lung Development, Growth, and Repair IAN COPLAND, KEITH TANSWELL, and MARTIN POST Departments of Pediatrics, Physiology, and Laboratory Medicine and Pathology, Lung Biology Research Programme, Hospital for Sick Children Research Institute, University of Toronto, Toronto, Ontario, Canada I. Overview This chapter presents basic principles and current perspectives on lung development, growth, and repair. Processes of injury described in subsequent chapters must be viewed in the context of these factors. Throughout life, the lungs are a dynamic organ system that attempts to adapt to stress and to repair injury to cells and tissue. Depending on the circumstances, these processes of adaptation and repair can mitigate pulmonary damage or exacerbate the progression of injury. Many of the phenomena occurring during pulmonary adaptation and repair recapitulate those involved in growth and development. This chapter introduces basic elements of lung structure, embryology, and cellular specification, including the effects of key transcription factors, growth factors, and physical forces. Coverage includes fundamental information on alveolarization, the growth of gas exchange tissue, and the pulmonary capillary bed. A description of relevant congenital abnormalities that lead to pulmonary hypoplasia is also provided. Concepts of pulmonary remodeling and repair pertinent to both prenatal and postnatal events are introduced, and their relevance and importance for specific aspects of acute and chronic lung injury are then detailed further in following chapters. II. Introduction Lung development can be subdivided into five stages: 1. Embryonic* period—development of major airways 2. Pseudoglandular period—development of airways to terminal bronchioles 3. Canalicular period—development of the acinus and vascularization 4. Terminal sac (saccular) period—subdivision of saccules by secondary crests 5. Alveolar period—the appearance of alveoli Although the morphological changes associated with lung evelopment are well characterized, the body of information regarding the molecular mechanisms that determine cellular fate, pattern formation, and growth during lung development are less

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clear. A better understanding of the molecular basis of pulmonary development will aid in understanding the etiology of relatively common foregut malformations (such as tracheoesophageal fistula and esophageal atresia) and less common congenital anomalies (such as tracheal stenosis, unilateral and bilateral lung agenesis, and alveolarcapillary dysplasia). Lung hypoplasia represents another common pulmonary malformation. Conditions that lead to pulmonary hypoplasia include premature rupture of the membranes (