(Lung Biology in Health and Disease, V. 137) Richard D Bland_ Jacqueline J Coalson-Chronic Lung...

LUNG BIOLOGY IN HEALTH AND DISEASE

Executive Editor

Claude LenfantDirector, National Heart, Lung, and Blood Institute

National Institutes of HealthBethesda, 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. Crystal3. Bioengineering Aspects of the Lung, edited by J. B. West4. Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane5. Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain,

D. F. Proctor, and L. M. Reid6. Development of the Lung, edited by W. A. Hodson7. Lung Water and Solute Exchange, edited by N. C. Staub8. Extrapulmonary Manifestations of Respiratory Disease, edited by E. D.

Robin9. Chronic Obstructive Pulmonary Disease, edited by T. L. Petty

10. Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris11. Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin12. The Lung in the Transition Between Health and Disease, edited by P. T.

Macklem and S. Permutt13. Evolution of Respiratory Processes: A Comparative Approach, edited

by S. C. Wood and C. Lenfant14. Pulmonary Vascular Diseases, edited by K. M. Moser15. Physiology and Pharmacology of the Airways, edited by J. A. Nadel16. Diagnostic Techniques in Pulmonary Disease (in two parts), edited by

M. A. Sackner17. Regulation of Breathing (in two parts), edited by T. F. Hornbein18. Occupational Lung Diseases: Research Approaches and Methods,

edited by H. Weill and M. Turner-Warwick19. Immunopharmacology of the Lung, edited by H. H. Newball20. Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by

B. L. Fanburg21. Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan22. Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treat-

ment, edited by L. S. Young23. Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Dis-

ease, edited by H. L. Atkins24. Acute Respiratory Failure, edited by W. M. Zapol and K. J. Falke25. 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 ExtrauterineLife, 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. Macklem30. The Pleura in Health and Disease, edited by J. Chrtien, J. Bignon, and

A. Hirsch31. Drug Therapy for Asthma: Research and Clinical Practice, edited by J.

W. Jenne and S. Murphy32. Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan33. The Airways: Neural Control in Health and Disease, edited by M. A.

Kaliner and P. J. Barnes34. Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke35. Respiratory Function of the Upper Airway, edited by O. P. Mathew and

G. Sant'Ambrogio36. Chronic Obstructive Pulmonary Disease: A Behavioral Perspective,

edited by A. J. McSweeny and I. Grant37. Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T.

Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams38. Pulmonary Vascular Physiology and Pathophysiology, edited by E. K.

Weir and J. T. Reeves39. Comparative Pulmonary Physiology: Current Concepts, edited by S. C.

Wood40. Respiratory Physiology: An Analytical Approach, edited by H. K. Chang

and M. Paiva41. Lung Cell Biology, edited by D. Massaro42. HeartLung Interactions in Health and Disease, edited by S. M. Scharf

and S. S. Cassidy43. Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited

by M. J. Hensley and N. A. Saunders44. Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky45. The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A.

Zimmerman46. Diagnostic Imaging of the Lung, edited by C. E. Putman47. Models of Lung Disease: Microscopy and Structural Methods, edited by

J. Gil48. Electron Microscopy of the Lung, edited by D. E. Schraufnagel49. Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J.

Barnes, and C. G. A. Persson50. Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and

F. Lemaire51. Lung Disease in the Tropics, edited by O. P. Sharma52. Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J.

Whipp and K. Wasserman53. Developmental Neurobiology of Breathing, edited by G. G. Haddad and

J. P. Farber54. Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H.

Anderson55. The Airway Epithelium, edited by S. G. Farmer and D. Hay

56. Physiological Adaptations in Vertebrates: Respiration, Circulation, andMetabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R.W. Millard

57. The Bronchial Circulation, edited by J. Butler58. Lung Cancer Differentiation: Implications for Diagnosis and Treatment,

edited by S. D. Bernal and P. J. Hesketh59. Pulmonary Complications of Systemic Disease, edited by J. F. Murray60. Lung Vascular Injury: Molecular and Cellular Response, edited by A.

Johnson and T. J. Ferro61. Cytokines of the Lung, edited by J. Kelley62. The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D.

Metcalfe63. Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler64. Cystic Fibrosis, edited by P. B. Davis65. Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center,

and V. A. Tkachuk66. Tuberculosis: A Comprehensive International Approach, edited by L. B.

Reichman and E. S. Hershfield67. Pharmacology of the Respiratory Tract: Experimental and Clinical Re-

search, edited by K. F. Chung and P. J. Barnes68. Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg,

J.-P. Martin, and R. Masse69. Pneumocystis carinii Pneumonia: Second Edition, edited by P. D.

Walzer70. Fluid and Solute Transport in the Airspaces of the Lungs, edited by R.

M. Effros and H. K. Chang71. Sleep and Breathing: Second Edition, edited by N. A. Saunders and C.

E. Sullivan72. Airway Secretion: Physiological Bases for the Control of Mucous Hy-

persecretion, edited by T. Takishima and S. Shimura73. Sarcoidosis and Other Granulomatous Disorders, edited by D. G.

James74. Epidemiology of Lung Cancer, edited by J. M. Samet75. Pulmonary Embolism, edited by M. Morpurgo76. Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach77. Endotoxin and the Lungs, edited by K. L. Brigham78. The Mesothelial Cell and Mesothelioma, edited by M.-C. Jaurand and J.

Bignon79. Regulation of Breathing: Second Edition, edited by J. A. Dempsey and

A. I. Pack80. Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall81. 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-Schne, andM. E. Schlfke

83. A History of Breathing Physiology, edited by D. F. Proctor84. Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W.

Taeusch85. 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 aviumComplex Infection: Progress in Research andTreatment, edited by J. A. Korvick and C. A. Benson

88. Alpha 1Antitrypsin Deficiency: Biology Pathogenesis Clinical Mani-festations 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. Guz91. Pulmonary Rehabilitation, edited by A. P. Fishman92. Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease,

edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski93. Environmental Impact on the Airways: From Injury to Repair, edited by

J. Chrtien and D. Dusser94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited

by A. J. Hickey95. Tissue Oxygen Deprivation: From Molecular to Integrated Function,

edited by G. G. Haddad and G. Lister96. The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers97. Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions,

edited by R. P. Schleimer, W. W. Busse, and P. M. OByrne98. Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch99. Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich

100. Lung Growth and Development, edited by J. A. McDonald101. Parasitic Lung Diseases, edited by A. A. F. Mahmoud102. Lung Macrophages and Dendritic Cells in Health and Disease, edited

by M. F. Lipscomb and S. W. Russell103. Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman104. Gene Therapy for Diseases of the Lung, edited by K. L. Brigham105. Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz

Clerch and D. J. Massaro106. Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M.

OByrne107. Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L.

Adjei and P. K. Gupta108. Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom109. Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M.

Orenstein and R. C. Stern110. Asthma and Immunological Diseases in Pregnancy and Early Infancy,

edited by M. Schatz, R. S. Zeiger, and H. N. Claman111. Dyspnea, edited by D. A. Mahler112. Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said113. Self-Management of Asthma, edited by H. Kotses and A. Harver114. Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J.

Gryglewski, and J. R. Vane115. Fatal Asthma, edited by A. L. Sheffer116. Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar117. Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W.

W. Busse118. 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. Rosenand J. M. Beck

120. Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-E.Dahln, 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. Mygind124. Lung Tumors: Fundamental Biology and Clinical Management, edited

by C. Brambilla and E. Brambilla125. Interleukin-5: From Molecule to Drug Target for Asthma, edited by C. J.

Sanderson126. Pediatric Asthma, edited by S. Murphy and H. W. Kelly127. Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F.

Wright128. Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M.

Foster129. Gastroesophageal Reflux Disease and Airway Disease, edited by M. R.

Stein130. Exercise-Induced Asthma, edited by E. R. McFadden, Jr.131. LAM and Other Diseases Characterized by Smooth Muscle Prolifera-

tion, edited by J. Moss132. The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller133. Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and

P. C. Zee134. Anticholinergic Agents in the Upper and Lower Airways, edited by S. L.

Spector135. Control of Breathing in Health and Disease, edited by M. D. Altose and

Y. Kawakami136. Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel137. Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J.

Coalson138. Asthma's Impact on Society: The Social and Economic Burden, edited

by K. B. Weiss, A. S. Buist, and S. D. Sullivan139. New and Exploratory Therapeutic Agents for Asthma, edited by M.

Yeadon and Z. Diamant140. Multimodality Treatment of Lung Cancer, edited by A. T. Skarin141. Cytokines in Pulmonary Disease: Infection and Inflammation, edited by

S. Nelson and T. R. Martin142. Diagnostic Pulmonary Pathology, edited by P. T. Cagle143. ParticleLung Interactions, edited by P. Gehr and J. Heyder144. Tuberculosis: A Comprehensive International Approach, Second Edi-

tion, Revised and Expanded, edited by L. B. Reichman and E. S.Hershfield

145. Combination Therapy for Asthma and Chronic Obstructive PulmonaryDisease, edited by R. J. Martin and M. Kraft

146. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Di-sease, edited by T. D. Bradley and J. S. Floras

147. Sleep and Breathing in Children: A Developmental Approach, edited byG. M. Loughlin, J. L. Carroll, and C. L. Marcus

148. Pulmonary and Peripheral Gas Exchange in Health and Disease, editedby J. Roca, R. Rodriguez-Roisen, and P. D. Wagner

149. Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter150. Nosocomial Pneumonia, edited by W. R. Jarvis151. Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P.

Barker152. Long-Term Mechanical Ventilation, edited by N. S. Hill153. Environmental Asthma, edited by R. K. Bush154. Asthma and Respiratory Infections, edited by D. P. Skoner155. Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bous-

quet, S. Rak, and R. A. Pauwels156. Genetic Models in Cardiorespiratory Biology, edited by G. G. Haddad

and T. Xu157. Respiratory-Circulatory Interactions in Health and Disease, edited by S.

M. Scharf, M. R. Pinsky, and S. Magder158. Ventilator Management Strategies for Critical Care, edited by N. S. Hill

and M. M. Levy159. 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. OCallaghan, andG. C. Smaldone

163. Inhaled Steroids in Asthma: Optimizing Effects in the Airways, edited byR. P. Schleimer, P. M. OByrne, 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, editedby 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. Albelda170. Disease Markers in Exhaled Breath, edited by N. Marczin, S. A. Kharito-

nov, M. H. Yacoub, and P. J. Barnes171. Sleep-Related Breathing Disorders: Experimental Models and Thera-

peutic Potential, edited by D. W. Carley and M. Radulovacki172. Chemokines in the Lung, edited by R. M. Strieter, S. L. Kunkel, and T.

J. Standiford173. Respiratory Control and Disorders in the Newborn, edited by O. P.

Mathew174. 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

ADDITIONAL VOLUMES IN PREPARATION

Therapeutic Targets in Airway Inflammation, edited by N. T. Eissa andD. Huston

Respiratory Infections in Asthma and Allergy, edited by S. Johnston andN. Papadopoulos

Acute Respiratory Distress Syndrome, edited by M. A. Matthay

Upper and Lower Respiratory Disease, edited by J. Corren, A. Togias,and J. Bousquet

Venous Thromboembolism, edited by J. E. Dalen

Acute Exacerbations of Chronic Obstructive Pulmonary Disease, editedby N. Siafakas, N. Anthonisen, and D. Georgopolous

Lung Volume Reduction Surgery for Emphysema, edited by H. E.Fessler, J. J. Reilly, Jr., and D. J. Sugarbaker

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

M A R C E l

MARCEL DEKKER, INC.

C H RC) N I C LUNG DISEASE IN

EARLY I N FANCY

Edited by

Richard D. Bland University of Utah School of Medicine

Salt Lake CXM Utah

Jacqueline J. Coalson University of Texas Health Sciencle Center

San Antonio, Texas

NEW YORK: - BASEL D E K K E R

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1999 by Taylor & Francis Group, LLCCRC Press is an imprint of Taylor & Francis Group, an Informa business

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INTRODUCTION

I believe there is general acceptance that chronic lung disease in early infancy hasits origin in abnormal lung development. One of the most common expressions ofabnormal lung development is bronchopulmonary dysplasia (BPD). Our appreci-ation of this condition is relatively recent: it developed just over 30 years agofollowing the seminal observations of Northway et al. in 1967 (1). Since then,considerable research has been done to clarify the cause of BPD, to treat it, andto understand its relationship to chronic lung disease in early infancy and later.

In 1979, the report of a workshop on BPD (2) provided a blueprint forresearch that, if followed, should have improved the condition of newborns withBPD. In the Foreword of this report, I wrote: We hope that the interested scien-tific communities will respond to the challenge that these recommendationsoffer.

About 10 years later, in 1988, Northway wrote: The short history of BPDhas coincided with a remarkable increase in the intensity of care provided notonly to premature infants with respiratory failure, but also to children and adultswith respiratory failure. And, he concluded later: History has focused on theoccurrence of BPD in the premature infant. In the future, that focus may verywell have to be broadened (3).

Since then, research has continued and its translation into better care hasaccelerated considerably. However, BPD has become a bigger public health prob-lem, largely because of the immense success of neonatologists in saving the livesof babies born more and more prematurely. Thus, the incidence and severity ofBPD have increased. Further, as noted by the editors of this volume in theirPreface, the features and patterns of the disease have changed greatly.

In a way, this book commemorates the 30th anniversary of Dr. Northwaysiii

iv Introduction

work, which brought to the attention of the research and medical communitiesa public health problem that has become more serious since that time. But, atthe same time, it is a celebration of the tremendous research accomplishmentsof the last 30 years. As mentioned previously, the field has become much morecomplex, but the prospects for solutions have also become greater. For example,we can watch with positive expectations our evolving knowledge about the roleof retinoic acid in the formation of alveoli!

I know for a fact that Drs. Richard Bland and Jacqueline Coalson commit-ted themselves wholeheartedly to the development and realization of this volume.The personal time they devoted to it has been considerable and, as we look atthe end product, we can only express admiration and gratitude. Indeed, the fieldis well served by this volume, which brought together experts in their fields.There is no doubt that this volume will be an inspiration to both researchers andclinicians. For the Lung Biology in Health and Disease series of monographs,this is another landmark for which I am most appreciative.

Claude Lenfant, M.D.Bethesda, Maryland

References

1. Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respiratorytherapy of hyaline-membrane disease: Bronchopulmonary dysplasia. N Engl J Med1967; 276: 357.

2. Workshop on Bronchopulmonary Dysplasia. J Ped 1979; 85(5).3. Northway WH. Historical perspectives in bronchopulmonary dysplasia. In: Merritt

TA, Northway WH, Boynston BP, eds. Bronchopulmonary Dysplasia. Oxford:Blackwell Scientific, 1988.

PREFACE

This book is about pulmonary pathology produced by progress in the practice ofperinatal pediatrics. Chronic lung disease in early infancy was an unknown entitylittle more than three decades ago. Its appearance coincided with the initial effortsat positive pressure mechanical ventilation to rescue infants who suffered life-threatening respiratory distress, usually from underdeveloped lungs. When North-way and associates first described the clinical, radiographic, and pathologicalfeatures of this disease, which they called bronchopulmonary dysplasia, few in-fants with respiratory failure survived, and most of those who did surviveweighed at least 2 kg at birth. In the intervening years, there has been remarkableprogress in our understanding, treatment, and prevention of acute respiratory dis-tress after premature birth. Important discoveries in both basic and applied bio-medical research paved the way for extraordinary success in the clinical care ofinfants who were born too soon. Widespread use of prenatal glucocorticoid andpostnatal surfactant treatment, acceptance of modest hypercapnia with less ag-gressive application of positive pressure breathing, improved nutritional support,and meticulous attention to detail in the delivery of intensive care have spawnedsurvival of extremely tiny, premature infants who are most vulnerable to experi-ence the persistent need for assisted ventilation. Thus, the incidence of this typeof chronic lung disease remains high, although the pattern of clinical signs andsymptoms, radiographic images, and pathological features of the disease havechanged considerably, probably reflecting the degree of lung immaturity of thesetiny infants, as well as the many modifications in their management that haveoccurred over the past several years.

This book is divided into five parts. Part I focuses on major clinical aspectsof the disease, with particular attention to its evolution over the past decade,

v

vi Preface

during which time rapid technological developments and widespread applicationsof new therapies, notably prenatal glucocorticoids and postnatal surfactants, havehad their greatest impact. Part II examines normal and abnormal alveolar andairway development. Part III focuses on both normal and abnormal developmentof lung circulation and interstitium. Part IV centers on mechanisms of injury andrepair, and, finally, Part V discusses relevant animal models for studying thedisease process during its evolution and during recovery.

Our goals in planning this book were to (1) present the important clinicaland pathological features of a disease that represents a major cause of long-termhospitalization, slow growth, and recurrent respiratory ailments in early child-hood; (2) provide a timely, comprehensive review of what is known about lungdevelopment, injury, and repair as they might relate to the pathogenesis of chroniclung disease of early infancy; (3) define what relevant information needs to belearned and how we might learn it; and (4) relate this information to potentialtherapeutic and preventive strategies. To accomplish these goals, we invitedworld-renowned experts from many scientific disciplines and medical fields tocontribute their knowledge and ideas on this important subject. We are extremelygrateful to the authors for their efforts, which we hope will facilitate better under-standing of how the lungs develop both structurally and functionally, how thisdevelopment may be altered as a result of injury and subsequent repair, and howthese processes may be modified by effective therapy or, better yet, prevention.

We are especially grateful to Sharon Marron for her outstanding administra-tive efforts in organizing the submission of chapters and ensuring successful com-pletion of this work.

Richard D. BlandJacqueline J. Coalson

CONTRIBUTORS

Steven H. Abman, M.D. Professor and Director, Pediatric Heart and LungCenter, University of Colorado School of Medicine, Denver, Colorado

Kurt Albertine, Ph.D. Professor, Departments of Pediatrics, Medicine, andNeurobiology/Anatomy, University of Utah Health Sciences Center, Salt LakeCity, Utah

Solomon Alkrinawi, M.D. Fellow, Pediatric Pulmonology, University of Man-itoba, Winnipeg, Manitoba, Canada

Michael Apkon, M.D., Ph.D. Assistant Professor, Department of Pediatricsand Cellular and Molecular Physiology, Yale University School of Medicine,New Haven, Connecticut

Ann M. Arvin, M.D. Lucile Packard Professor of Pediatrics and Microbiology/Immunology, Stanford University School of Medicine, Stanford, California

Philip L. Ballard, M.D., Ph.D. Professor of Pediatrics, Division of Neonatol-ogy, University of Pennsylvania School of Medicine, and Childrens Hospital ofPhiladelphia, Philadelphia, Pennsylvania

Roberta A. Ballard, M.D. Professor of Pediatrics and Obstetrics and Gynecol-ogy, Division of Neonatology, University of Pennsylvania School of Medicine,Childrens Hospital of Philadelphia, Philadelphia, Pennsylvania

vii

viii Contributors

Eduardo Bancalari, M.D. Professor of Pediatrics, Division of Neonatology,Department of Pediatrics, University of Miami School of Medicine, Miami,Florida

William E. Benitz, M.D. Associate Professor, Divisions of Neonatal and De-velopmental Medicine, Department of Pediatrics, Stanford University School ofMedicine, Stanford, California

William R. Berrington Research Associate, University of Alabama at Bir-mingham, Birmingham, Alabama

Richard D. Bland, M.D. Fields Professor of Pediatrics, University of UtahSchool of Medicine, Salt Lake City, Utah

John F. Bohnsack, M.D. Associate Professor, Department of Pediatrics, Uni-versity of Utah Health Sciences Center, Salt Lake City, Utah

Shilpa Buch Assistant Professor of Pediatrics, University of Toronto, The Hos-pital for Sick Children, Toronto, Ontario, Canada

David P. Carlton, M.D. Associate Professor, Department of Pediatrics, Uni-versity of Utah Health Sciences Center, Salt Lake City, Utah

Victor Chernick, M.D., F.R.C.P.C. Professor of Pediatrics, University ofManitoba, Winnipeg, Manitoba, Canada

Jacqueline J. Coalson, Ph.D. Professor, Department of Pathology, Universityof Texas Health Science Center, San Antonio, Texas

Peter Dargaville, M.D. Royal Childrens Hospital, Victoria, Australia

Robert A. De Lemos* Hastings Professor of Pediatrics, University of SouthernCalifornia, Los Angeles, California

David K. Edwards, M.D. Professor of Radiology and Pediatrics, Universityof California Medical School, San Diego, California

Eric C. Eichenwald, M.D. Assistant Professor, Harvard Medical School andBrigham and Womens Hospital, Boston, Massachusetts

*Deceased.

Contributors ix

Leland L. Fan, M.D. Professor of Pediatrics, Baylor College of Medicine,Houston, Texas

Henry Jay Forman, Ph.D. Charles Krown Professor of Molecular Pharmacol-ogy and Toxicology, University of Southern California, Los Angeles, California

H. Lee Frank, M.D., Ph.D. Professor of Medicine and Pediatrics, PulmonaryResearch Center, University of Miami School of Medicine, Miami, Florida

Bruce A. Freeman, Ph.D. Professor and Vice-Chair of Research, Departmentof Anesthesiology and Department of Biochemistry and Molecular Genetics, Uni-versity of Alabama at Birmingham, Birmingham, Alabama

Michael R. Gomez, M.D. Assistant Professor of Pediatrics, Santa Rosa Chil-drens Hospital, San Antonio, Texas

Alvaro Gonzalez, M.D. Instructor, Department of Pediatrics, University ofMiami School of Medicine, Miami, Florida

Peter Groneck, M.D. Department of Pediatrics, Childrens Hospital of the Cityof Cologne, Cologne, Germany

Imad Y. Haddad Department of Anesthesiology, University of Alabama atBirmingham, Birmingham, Alabama

Thomas N. Hansen, M.D. Professor and Chairman, Department of Pediatrics,Ohio State University, and Chief Executive Officer, Childrens Hospital, Colum-bus, Ohio

Samuel Hawgood, M.B., B.S. Professor of Pediatrics, Pediatrics and Cardio-vascular Research Foundation, University of California, San Francisco, Cali-fornia

Sheila G. Haworth, M.D., F.R.C.Path., F.R.C.P., F.A.C.C. British HeartFoundation Professor of Developmental Cardiology, Institute of Child Health,London, England

Thomas A. Hazinski, M.D. Professor and Vice-Chair, Department of Pediat-rics, Vanderbilt University Medical Center, Nashville, Tennessee

W. Alan Hodson, M.D. Professor of Pediatrics, Division of Neonatal Biology,Department of Pediatrics, University of Washington, Seattle, Washington

x Contributors

John R. Hoidal, M.D. Professor, Department of Medicine, University of Utah,Salt Lake City, Utah

Mari K. Hoidal, M.S. Research Associate, Department of Medicine, Univer-sity of Utah, Salt Lake City, Utah

Alan H. Jobe, M.D., Ph.D. Professor of Pediatrics, Division of PulmonaryBiology, Childrens Hospital Medical Center, Cincinnati, Ohio

Richard J. King, Ph.D. Professor, Department of Physiology, University ofTexas Health Science Center at San Antonio, San Antonio, Texas

Michael T. Kinter, Ph.D. Research Assistant Professor, Departments of Mi-crobiology and Pathology, University of Virginia Health Science Center, Char-lottesville, Virginia

Thomas R. Korfhagen Associate Professor, Department of Pediatrics, Univer-sity of Cincinnati College of Medicine, and Childrens Hospital Medical Center,Cincinnati, Ohio

George Lister, M.D. Professor, Departments of Pediatrics and Anesthesiology,Yale University School of Medicine, New Haven, Connecticut

Mingyao Liu University of Toronto, The Hospital for Sick Children, Toronto,Ontario, Canada

Diane E. Lorant Assistant Professor, Division of Neonatology, Department ofPediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah

Alma Martinez, M.D., M.P.H. Assistant Professor, Department of Pediatrics,University of California, San Francisco, California

Donald J. Massaro, M.D. Cohen Professor of Pulmonary Research, Depart-ment of Medicine, Georgetown University School of Medicine, Washington,D.C.

Gloria D. Massaro, M.D. Professor, Department of Pediatrics, GeorgetownUniversity School of Medicine, Washington, D.C.

Sadis Matalon, Ph.D. Professor, Department of Anesthesiology, University ofAlabama at Birmingham, Birmingham, Alabama

Contributors xi

Rodrigo A. Nehgme, M.D. Assistant Professor, Department of Pediatrics, YaleUniversity School of Medicine, New Haven, Connecticut

William H. Northway, Jr., M.D. Professor Emeritus of Radiology and Pediat-rics, Lucile Packard Childrens Hospital at Stanford, Palo Alto, California

Howard B. Panitch, M.D. Associate Professor of Pediatrics, University ofPennsylvania School of Medicine, and Division of Pulmonary Medicine, Chil-drens Hospital of Philadelphia, Philadelphia, Pennsylvania

Bruce R. Pitt, Ph.D. Professor, Department of Pharmacology, University ofPittsburgh School of Medicine, Pittsburgh, Pennsylvania

Martin Post, Ph.D., D.V.M. Professor of Pediatrics, University of Toronto,The Hospital for Sick Children, Toronto, Ontario, Canada

Marlene Rabinovitch, M.D., R.F.C.P.(C) Professor, University of Toronto,and Director, Department of Cardiovascular Research, The Hospital for SickChildren, Toronto, Ontario, Canada

Scott H. Randell, Ph.D. Research Assistant Professor, Cystic Fibrosis/Pulmo-nary Research and Treatment Center, University of North Carolina, Chapel Hill,North Carolina

David J. Riley, M.D. Professor, Department of Medicine, University of Medi-cine and Dentistry of New JerseyRobert Wood Johnson Medical School, Pis-cataway, New Jersey

Robert J. Roberts, M.D.* Professor and Chairman, Department of Pediatrics,University of Virginia Health Science Center, Charlottesville, Virginia

Timothy W. Robison, Ph.D. Food and Drug Administration, Bethesda, Mary-land

Steven R. Seidner, M.D. Associate Professor, Department of Pediatrics, Uni-versity of Texas Health Science Center, San Antonio, Texas

Thomas H. Shaffer, Ph.D. Professor, Departments of Physiology and Pediat-rics, Temple University School of Medicine, Philadephia, Pennsylvania

*Deceased.

xii Contributors

Michael P. Sherman, M.D. Professor and Chief, Division of Neonatology,Department of Pediatrics, University of California, Davis, California

Charles Vincent Smith, Ph.D. Professor, Department of Pediatrics, BaylorCollege of Medicine, Houston, Texas

Ilene R. S. Sosenko, M.D. Professor, Division of Neonatology, Department ofPediatrics, University of Miami School of Medicine, Miami, Florida

Christian P. Speer, M.D., F.R.C.P.(E) Professor, Department of Pediatrics,University of Wurzburg, Wurzburg, Germany

Mildred T. Stahlman, M.D. Professor, Department of Pediatrics, VanderbiltUniversity School of Medicine, Nashville, Tennessee

Ann R. Stark, M.D. Associate Professor, Department of Pediatrics, HarvardUniversity, and Childrens Hospital, Boston, Massachusetts

H. William Taeusch, M.D. Professor, Department of Pediatrics, University ofCalifornia, San Francisco, California

A. Keith Tanswell, M.B., M.R.C.P.(UK), F.R.C.P.(C) Professor, Universityof Toronto, Division of Neonatology, The Hospital for Sick Children, Toronto,Ontario, Canada

Margaret M. Tarpey Associate Professor, Department of Anesthesiology,University of Alabama at Birmingham, Birmingham, Alabama

Michael J. Thomas, Ph.D. Professor of Biochemistry, Bowman Gray Schoolof Medicine, Wake Forest University, Winston-Salem, North Carolina

Samuel J. Tilden, M.D. Professor, University of Alabama at Birmingham, Bir-mingham, Alabama

William E. Truog, M.D. Professor, Department of Pediatrics, University ofMissouri, Kansas City, Missouri

Stephen E. Welty, M.D. Assistant Professor, Department of Pediatrics, BaylorCollege of Medicine, Houston, Texas

Carl W. White, M.D. Professor, Department of Pediatrics, University of Colo-rado Health Sciences Center, Denver, Colorado

Contributors xiii

Jeffrey A. Whitsett, M.D. Professor, Division of Pulmonary Biology, Depart-ment of Pediatrics, University of Cincinnati College of Medicine, and ChildrensHospital Medical Center, Cincinnati, Ohio

Stephen L. Young, M.D. Professor, Department of Medicine, Duke UniversityMedical Center, Durham, North Carolina

Sha Zhu Postdoctoral Fellow, University of Alabama at Birmingham, Bir-mingham, Alabama

CONTENTS

Introduction (Claude Lenfant) iiiPreface vContributors vii

Part One CLINICAL ASPECTS

1. Historical Perspective: Early Observations and SubsequentEvolution of Bronchopulmonary Dysplasia 1William H. Northway, Jr.

I. Introduction and Background 1II. Historical Perspective 2

III. Early Observations 5IV. The Evolution of BPD 8

References 14

2. Epidemiology of Bronchopulmonary Dysplasia: Clinical RiskFactors and Associated Clinical Conditions 21Alma Martinez, Peter Dargaville, and H. William Taeusch

I. Introduction 21II. Major Perinatal Clinical Risk Factors for BPD 22

III. Clinical Risk Scoring Systems 29IV. Postnatal Factors That Affect BPD 32

xv

xvi Contents

V. Summary 36References 36

3. Clinical Course and Lung Function Abnormalities DuringDevelopment of Neonatal Chronic Lung Disease 41Eduardo Bancalari and Alvaro Gonzalez

I. Introduction 41II. Definition and Incidence 42

III. Clinical Presentation 43IV. Differential Diagnosis of CLD 53V. Lung Function During Development of CLD 54

VI. Therapeutic Interventions and Lung Function DuringDevelopment of CLD 57References 59

4. Radiographic Features of BPD and Potential Applicationof New Imaging Techniques 65David K. Edwards and William H. Northway, Jr.

I. Introduction 65II. The Radiographic Progression of BPD 65

III. BPD as a Chronic Lung Disease 68IV. New Imaging Techniques 72V. Potential Applications 74

References 79

5. Pathology of Chronic Lung Disease of Early Infancy 85Jacqueline J. Coalson

I. Introduction 85II. Comparison of Classic BPD Pathology with BPD

Pathology in the 1990s 86III. Major Differences in Old BPD Versus New BPD

Pathology: Airway and Interstitial Disease 101IV. Alveolar Hypoplasia and Vascular Dysmorphic Changes:

The Consistent Findings in New BPD 108V. Pathogenesis of BPD in the 1990s 114

VI. Summary 117References 118

Contents xvii

6. The Usefulness of Bronchoalveolar Lavage in Infantswith Evolving Chronic Lung Disease 125Carl W. White and Leland L. Fan

I. Introduction 125II. General Considerations 126

III. Inflammation: Marker or Protagonist of Injury? 132IV. Clinical Usefulness of BAL in BPD 139V. Conclusion 140

References 141

7. Inflammatory Mediators in Neonatal Lung Disease 147Christian P. Speer and Peter Groneck

I. Introduction 147II. Neutrophils and Macrophages 148

III. Neutrophil and Macrophage Recruitment 149IV. Cytokines 150V. Elastolytic Damage 152

VI. Inflammatory Mediators and Pulmonary Infections 153VII. Pulmonary Protein Leaks 154

VIII. Oxygen Toxicity 155IX. Conclusions and Outlook 156

References 157

8. Infection in the Pathogenesis of Bronchopulmonary Dysplasia 163William E. Benitz and Ann M. Arvin

I. Introduction 163II. Epidemiological Correlations 164

III. Pathogenetic Mechanisms 167References 169

9. Ventilation Strategies and Bronchopulmonary Dysplasia 173W. Alan Hodson

I. Introduction 173II. Barotrauma Versus Volutrauma 174

III. Site of Pathology and Ventilatory Strategy 176IV. Modes of Conventional Ventilators 181

xviii Contents

V. High-Frequency Ventilation 183VI. Strategies to Minimize Barotrauma 186

VII. Liquid Ventilation 192VIII. Weaning from Mechanical Ventilation 195

IX. Other Forms of Respiratory Support 196X. Future Needs 198

XI. Summary 199References 200

10. Effect of Respiratory Care Practices on the Developmentof Bronchopulmonary Dysplasia 209Michael R. Gomez and Thomas N. Hansen

I. Introduction 209II. Gas Temperature and Humidity 210

III. Aspiration 229IV. Conclusions 232

References 233

11. Influence of Surfactant Replacement on Developmentof Bronchopulmonary Dysplasia 237Alan H. Jobe

I. Statement of the Question 237II. Review of the Clinical Data 238

III. Why Should Surfactant Treatments Decrease BPD? 241IV. Why Surfactant Treatment Might Not Affect the

Incidence of BPD 246V. Summary 251

References 252

12. Drug Treatment for Established BPD 257Thomas A. Hazinski

I. Introduction 257II. Oxygen Therapy 259

III. Diuretic Therapy 260IV. Inhaled Bronchodilator Therapy 264V. Anti-Inflammatory Therapy 267

VI. Nutrition Therapy 269

Contents xix

VII. Other Drug Treatments for BPD 272VIII. Future Research Directions 273

IX. Summary 275References 276

13. Nutritional Issues in Chronic Lung Disease of PrematureInfants 285Ilene R.S. Sosenko, Michael T. Kinter, and Robert J. Roberts

I. Introduction 285II. Negative Influence of General Undernutrition and

Protein Malnutrition on Oxygen-Induced Lung Injury 286III. Lipid and Oxygen-Induced Lung Injury: Helpful or

Harmful? 287IV. Influence of Additional Nutrients (Inositol, Selenium,

and Vitamin A) on Oxygen-Induced Lung Injury 291V. Conclusion 293

References 293

14. Pulmonary Function in BPD and Its Aftermath 297Eric C. Eichenwald and Ann R. Stark

I. Introduction 297II. Clinical Evaluation of Infants and Children with BPD 298

III. Growth Failure in Infants with BPD 299IV. Exacerbations with Intercurrent Illness 300V. Techniques, Interpretation, and Limits of Pulmonary

Function Testing in Infants with BPD 301VI. Pulmonary Function in BPD: Infancy and Beyond 306

VII. Conclusions and Future Directions 313References 314

15. Cardiovascular Abnormalities in BronchopulmonaryDysplasia 321Michael Apkon, Rodrigo A. Nehgme, and George Lister

I. Introduction 321II. Disturbances in Cardiovascular Function 323

III. Therapeutic Strategies 336IV. Summary 346

References 346

xx Contents

16. Long-Term Recovery from Bronchopulmonary Dysplasia 357Solomon Alkrinawi and Victor Chernick

I. Introduction 357II. Physical Examination 359

III. Pulmonary Function 359IV. Airway Hyperreactivity 361V. Radiographic Study of the Chest 362

VI. Concluding Remarks 364References 364

17. The Goal: Prevention of BPD 367Mildred T. Stahlman

I. Introduction 367II. Predisposing Factors 369

References 374

Part Two NORMAL AND ABNORMAL ALVEOLARAND AIRWAY DEVELOPMENT

18. Unique Features of the Immature Lung That Make ItVulnerable to Injury 377Scott H. Randell and Stephen L. Young

I. Introduction 377II. The Airways 378

III. The Parenchyma 387References 396

19. Hormonal Effects on Lung Maturation and Disease 405Philip L. Ballard and Roberta A. Ballard

I. Introduction 405II. Prenatal Corticosteroid Therapy and Newborn Lung

Disease 406III. Effects of Thyroid Hormones on Lung Maturation 408IV. Combined Glucocorticoid and Thyroid Hormone

Treatment 409

Contents xxi

V. Clinical Trials of Antenatal Corticosteroid Plus TRHTherapy 419


20. Mechanisms and Physiological Sequelae of Reactive SpeciesInjury to the Alveolar Epithelium 431Imad Y. Haddad, Sha Zhu, Samuel J. Tilden, and Sadis Matalon

I. Introduction and Purpose 431II. Structure of the Newborn and Adult Alveolar Epithelium 432

III. Oxidant Stress in the Developing Lung 433IV. Biology of Reactive Oxygen and Nitrogen Species 434V. NO-Derived Effects on the Alveolar Epithelium 439

VI. Lesson from Basic Research: Development of RationalTherapeutic Interventions to Limit Oxidant Injury 449References 450

21. Surfactant in Chronic Lung Injury 457Richard J. King and Samuel Hawgood

I. Introduction 457II. Composition and Functions of Pulmonary Surfactant 458

III. Experimental Studies on Surfactant in Chronic LungInjury 462

IV. Involvement of Surfactant in Patients with ChronicLung Injury 469

V. Conclusions 471References 472

22. The Regulation of the Formation of Pulmonary Alveoli 479Donald J. Massaro and Gloria D. Massaro

I. Introduction 479II. Architectural Maturation of the Lungs Gas-Exchange

Region: From Saccules to Alveoli 480III. Formation of Alveoli 481IV. Relation of Experimental Work to the Lung and Its

Development in Prematurely Born Infants withBronchopulmonary Dysplasia 488References 489

xxii Contents

23. Factors Mediating Cell Growth in Lung Injury 493A. Keith Tanswell, Shilpa Buch, Mingyao Liu, and Martin Post

I. Introduction 493II. Regulation of Cell Division 494

III. Regulation of Normal Lung Growth by Growth Factors 498IV. The Influence of Physical Factors on Lung Cell Growth 503V. The Influence of Oxygen on Lung Cell Growth 506

VI. EpithelialMesenchymal Interactions in Lung Injury 509VII. Specific Growth Factors in Lung Injury 510

VIII. Problems of Interpretation 513IX. Foci for Future Research 514

References 515

24. Developmental Airway Structure and Function in Healthand Chronic Lung Injury 535Howard B. Panitch and Thomas H. Shaffer

I. Introduction 535II. Developmental Morphology 536

III. Functional Characteristics of the Immature Airway 547IV. Clinical Assessment of Airway Function 555V. Summary 561

References 562

Part Three NORMAL AND ABNORMAL DEVELOPMENTOF THE LUNG CIRCULATION AND INTERSTITIUM

25. Lung Development and the Effects of Chronic Hypoxia 569Sheila G. Haworth

I. Introduction 569II. Normal Development of the Human Lung 569

III. Effect of Chronic Hypoxia on Lung Development 579IV. The Future: Where Do We Go from Here? 589

References 591

26. Altered Development of the Pulmonary Circulationin Chronic Lung Injury 597Marlene Rabinovitch

I. Introduction 597II. Structural Changes in Pulmonary Arteries 598

III. Acute and Chronic Infection 598

Contents xxiii

IV. Hypoxia 609V. Oxygen Toxicity and Barotrauma 610

VI. High Flow and Pressure 610VII. Chronic Lung Injury: Questions to Be Solved 614

References 614

27. Pulmonary Hypertension in Chronic Lung Disease ofInfancy: Pathogenesis, Pathophysiology, and Treatment 619Steven H. Abman

I. Introduction 619II. Perinatal Pulmonary Circulation: Developmental Aspects 621

III. Effects of Lung Injury on the Developing PulmonaryCirculation 626

IV. Pulmonary Hypertension in Premature Neonates withSevere RDS 633

V. Pulmonary Hypertension in CLD of Infancy 636VI. Conclusions and Future Directions 649

References 650

28. Connective Tissues in Lung Development and Diseasesin Early Infancy 669David J. Riley

I. Introduction 669II. Extracellular Matrix: General 670

III. ECM Proteins in Lung Development 685IV. Connective Tissue Changes in Lung Diseases of Early

Infancy 688V. Future Directions 695

References 697

29. Pulmonary Edema After Premature Birth: Progressionfrom Acute to Chronic Lung Disease 711Richard D. Bland and David P. Carlton

I. Introduction 711II. Lung Fluid Balance During Fetal Development 713

III. Postnatal Lung Fluid Balance 718IV. Lingering Questions 735

References 737

xxiv Contents

Part Four MECHANISMS OF LUNG INJURY AND REPAIRDURING DEVELOPMENT

30. Molecular Mechanisms of Oxygen-Induced Lung Injury 749Charles Vincent Smith and Stephen E. Welty

I. Introduction 749II. Possible Roles of Hyperoxic Lung Injury in CLD 750

III. Reactive Oxygen Species in Hyperoxic Lung Injury 753IV. Biomarkers of Reactive Oxygen Species in Biological

Systems 754V. Roles of Iron Metabolism in Reactive Oxygen-Mediated

Tissue Injury 768VI. Summary and Conclusions 769

References 769

31. Assessment of Tissue Injury from Reactive OxygenMetabolites 779Michael J. Thomas, Timothy W. Robison, andHenry Jay Forman

I. Introduction 779II. Methods 783

III. Future Directions 786References 786

32. Chronic Lung Disease of Early Infancy: Role of Neutrophils 793Diane E. Lorant, Kurt Albertine, and John F. Bohnsack

I. Introduction 793II. Mechanisms of Neutrophil-Mediated Injury and

Recruitment to the Lung 793III. Pathological and Clinical Studies of Neutrophil

Involvement in BPD 796IV. The Role of Neutrophils in Animal Models of BPD 801V. Conclusions 804

References 806

33. The Role of Pulmonary Macrophages in Chronic LungDisease of Early Infancy 813Michael P. Sherman and William E. Truog

I. Introduction 813II. Emergence of Pulmonary Macrophage Populations and

the Pathophysiology of CLD of Early Infancy 814

Contents xxv

III. The Role of Pulmonary Macrophages and Lung Infectionin the Pathophysiology of CLD of Early Infancy 816

IV. Interactions of Lung Macrophages with Other PulmonaryCells by Direct Cell-to-Cell Communication andSecretory Activity 822

V. Limitations to the Study of Alveolar Macrophages in CLDof Early Infancy and Future Directions 830References 832

34. Oxidants and Antioxidants: What Role Do They Play inChronic Lung Disease? 841H. Lee Frank and Ilene R.S. Sosenko

I. Introduction 841II. General Principles of Oxidants and Antioxidants 842

III. Evidence Linking Oxygen Radicals and CLD 845IV. Development of the AOE System in the Fetal Lung 845V. Vulnerability of the Premature Infant Relative to

Antioxidant Defenses 847VI. Experimental and Potential Therapeutic Modification of

Antioxidant Defenses 849VII. Oxygen Toxicity, Antioxidant Enzymes, and CLD:

Unanswered Questions and Future Clinical Applications 852References 853

35. Proteolytic Enzymes and Their Inhibitors in Lung Healthand Disease 859John R. Hoidal and Mari K. Hoidal

I. Introduction 859II. Classification of Proteases 860

III. Control of Proteolytic Enzymes 863IV. Functions of Proteolytic Enzymes 868V. Proteases and Pulmonary Diseases 870

VI. Proteases and Chronic Lung Disease of Early Infancy 872VII. What Lies Ahead? 873

References 875

36. Site- and Mechanism-Directed Interventions for Tissue FreeRadical Injury 883William R. Berrington, Margaret M. Tarpey, Bruce A. Freeman,and Bruce R. Pitt

I. Introduction 883II. Oxidant-Protective Reactions of Nitric Oxide 884

xxvi Contents

III. Targeting Catalytic Radical Scavengers to theExtracellular Compartment 890

IV. Targeting Catalytic Radical Scavengers to theIntracellular Compartment 894

V. Gene Therapy Strategies for Enhancing PulmonaryAntioxidant Defenses 898


Part Five MODELS OF LUNG INJURY AND REPAIRDURING DEVELOPMENT

37. Genetic Models for the Study of AutocrineParacrineSignaling in Lung Development and Repair 911Jeffrey A. Whitsett and Thomas R. Korfhagen

I. Introduction 911II. Role of Fibroblast Growth Factors 912

III. TGF- and EGF-R Signaling and Pulmonary Fibrosisand Airspace Remodeling 917

IV. Bronchopulmonary Dysplasia 923V. Summary 924

References 924

38. Animal Models of Chronic Lung Injury 927Jacqueline J. Coalson, Steven R. Seidner, and Robert A. De Lemos

I. Introduction 927II. What Is the Human Disease That Needs to Be Modeled? 928

III. Contributors to the Development of BPD 929IV. Potential Uses of Transgenic Models for Future Studies 941V. Summary and Future Needs 945

References 946

Author Index 957Subject Index 1043

1Historical PerspectiveEarly Observations and Subsequent Evolutionof Bronchopulmonary Dysplasia

WILLIAM H. NORTHWAY, Jr.

Lucile Packard Childrens Hospital at StanfordPalo Alto, California

I. Introduction and Background

Bronchopulmonary dysplasia (BPD) was first described in 1967 in a report docu-menting the clinical, radiologic, and pathological changes seen in prematurelyborn infants with severe respiratory distress syndrome (RDS) who had beentreated with prolonged mechanical ventilation and warm, humidified 80100%concentrations of oxygen (1). This report documented the appearance of a new,chronic pulmonary syndrome that was associated with the use of mechanicalventilation and supplemental oxygen treatment of these infants for longer than6 days. In 1967, RDS was the leading cause of death in newborn infants. Thenatural course of RDS before the use of mechanical ventilation was either deathby 45 days of age or complete recovery by 7 days of age, with a normal chestradiograph (2). The use of mechanical ventilation and supplemental oxygen treat-ment for respiratory failure secondary to RDS in the newborn infant was a contin-uation of the historical desire to decrease newborn infant mortality by employingimprovements in medical care and applications of new technology.

1

2 Northway

II. Historical PerspectiveA. Care of the Prematurely Born Infant

Modern care of the prematurely born infant began in the 19th century and waspromoted in Paris by the obstetrician Stephane Tarnier and his pupil Pierre Con-stant Budin (3). Before the 19th century, high infant mortality was consideredinevitable, and the death of prematurely born infants was only a minor part ofthe problem. An improvement in infant mortality by warming premature infantswas first noted in 1829 by Villerme and Edwards (4). A closed incubator wasfirst introduced at the Maternite at Port Royal in Paris where Tarnier was surgeonin chief in 1881 (5). The diagnosis of prematurity on the basis of birth weightwas first described in 1872 (6). It was not until 1896 that a special hospital unitto prevent the spread of infection in premature infants was designed, which in-cluded hand washing and gowning of nurses before they handled the infants (7).Prematurity was still the most important cause of death in infants younger than1 year of age in the 1930s and 1940s in the United States (3). Over half of thedeaths caused by prematurity occurred in the first 24 hr of life (8,9). In the 1960smost pregnant women were being delivered in hospitals, rather than at home,and modern investigations of infant metabolism and feeding had begun (10,11).Penicillin and sulfonamides, as well as other antibiotics, had been developed andwere used in caring for prematurely born infants. Even with all these advances,minimal handling and minimal treatment of sick premature infants remained thestandard of care (12).

B. Hyaline Membrane Disease

Hyaline membranes in the lungs of newborn infants dying of respiratory failurewere first described by Hochheim in 1903 (13). These membranes were attributedto aspiration of amniotic sac contents by Hochheim and others, and it was notuntil the critical review of this theory by Miller and Hamilton in 1949 that intensi-fied investigation of this entity occurred (14). At about the same time it becameapparent that hyaline membrane disease principally affected liveborn prematureinfants and infants of diabetic mothers, and there was an association of fetalanoxia with the disorder. Even as late as 1957, hyaline membrane disease, orrespiratory distress syndrome (RDS) as it was subsequently named, was not in-cluded in the standard nomenclature of disease (15).

C. Diagnostic Radiology

The antemortem diagnosis of RDS could not be established until the developmentof modern chest radiographic techniques. Following the discovery of x-rays inDecember 1895 by Conrad Roentgen (16), their use for medical diagnosis spreadrapidly throughout the world. Advances in this technology also occurred quickly,

Historical Perspective of BPD 3

so that by the early 1950s, with improvements in x-ray tubes, film, intensifyingscreens, and equipment, it became possible to see fine anatomical detail in thelungs of newborn infants with RDS. Radiologic changes in the lungs of infantswith RDS were described for the first time in 1953 by Donald and Lord (17). Inthe same year, Donald and Steiner, demonstrated the classic reticular granularpattern of density in the lungs with air bronchograms in infants with proven RDS(18). Peterson and Pendleton, 2 years later, differentiated the radiologic patternof RDS from aspiration pneumonia, which allowed the establishment of a firmdiagnoses of these disorders in nonfatal cases (2). They also described the radio-logic course of RDS as being either progressive opacification of the lungs, withdeath in 35 days, or complete radiographic clearing in 710 days.

D. Mechanical Ventilation

The modern era of mechanical ventilation of newborn infants with respiratoryfailure began in 1953 when Donald and Lord described the use of a negative-pressure ventilator for prolonged artificial ventilation of the newborn infant (Fig.1) (17,19). The history of resuscitation, however, extends back at least to 400bc, with a description of cannulation of the trachea to support ventilation byHippocrates (20). Chaussier, in 1806, developed the intralaryngeal tube for resus-citation of newborn infants (21). Truehead and Fell-ODwyer subsequently devel-oped ventilating apparatuses for use in newborn infants (22), and Champneys,in 1882, characterized the pressures required to produce interstitial emphysemaand pneumothorax in stillborn human infants (23).

E. Oxygen

Oxygen was first isolated by Joseph Priestley in 1771 (24), and was first usedexperimentally in newborn infants with respiratory difficulty in 1780 by Chaus-sier (25). Smith definitively described pulmonary oxygen toxicity in mice in 1899(26). Although Bonnair published the first detailed clinical report of oxygen ther-apy in premature infants with cyanosis in 1891 (27), oxygen therapy did notbecome common practice in the care of premature infants until the 1930s and1940s. It was not until the 1940s that perinatal asphyxia was appreciated as amajor cause of neurological damage and death in the newborn (28). The highmortality rate from respiratory failure in premature infants contributed to theroutine use of oxygen therapy in the care of all premature infants by the late1940s. Use of supplemental oxygen was subsequently restricted when it wasfound that treatment with a high concentration of supplemental oxygen was asso-ciated with the appearance of retrolental fibroplasia (29). By 1962 it was recom-mended that no more than 40% oxygen be used in treating premature infants(30).

4 Northway

Figure 1 The modern era of prolonged mechanical ventilation of the newborn infantbegan with the apparatus for amplifying natural respiration used by Donald and Lordin 1953. (From Ref. 105.)

F. Prologue to BPD

A reevaluation of the therapy for RDS was stimulated by the demonstration byAvery and Mead in 1959 that the lungs of infants dying of RDS behaved asthough they lacked surface-active material (31). Avery and Oppenheimer, in 1960(32), found that deaths from RDS were increased when no or very little supple-mental oxygen was used as treatment compared with an earlier period in whichoxygen was used in higher concentration. These findings encouraged pediatri-cians to treat premature infants with RDS and respiratory failure with mechanicalventilation and concentrations of supplemental oxygen higher than 40% whilemonitoring arterial Po2.

The first premature infant research center, sponsored by the National Insti-


tutes of Health (NIH), was established at Stanford University Medical Center in1962. The first moribund infant with severe RDS was treated there with mechani-cal ventilation and supplemental oxygen therapy in 1963 by Drs. Vernon Thomasand Joe Daily, and the infant survived (33). The mechanical ventilator used hadonly two concentration settings for oxygen, 40% and 100%. The respiratory effec-tiveness of such treatment was measured, at that time, by the pH and the Paco2of arterialized capillary blood, and the infants skin color.

Other newborn nurseries were having similar success with artificial ventila-tion and supplemental oxygen treatment of prematurely born infants with RDS.A series of 52 infants with RDS treated with negative-pressure ventilation andoxygen supplementation by Shepard and co-workers was reported in an abstractin 1964, in which 23 of the infants, when examined at ages 6 months to 61/2years, had radiographic findings said to be compatible with pulmonary fibrosis(34). Their findings were questioned in a discussion following the presentation,and a more complete presentation of the abstract was not published. That sameyear, Robertson and associates reported on the late stages of pulmonary hyalinemembrane disease of the newborn (35). They demonstrated thickened alveolarwalls, with an increase of fibroblasts and excess of reticulin or collagen fibersin three infants who died at 13, 21, and 23 days of life, and in one studied by lungbiopsy in the eighth week of life. Two of these patients had received prolongedintermittent positive-pressure ventilation (IPPV) with high concentrations of oxy-gen. Emphysematous blebs and patchy infiltrate developed on early chest radio-graphs of their oldest living patient who had been treated with high positivepressure and 100% oxygen. These radiographic findings changed to small areasof atelectasis by 2 months of life. This infant had clinical signs of pulmonarydisease at 2 months of age. This may have been the earliest clinical and radio-graphic description of BPD.

III. Early Observations

The original population of prematurely born infants with severe RDS in whichBPD was recognized at Stanford University Medical Center were moribund andventilated with intermittent positive-pressure ventilation and humidified 80100% oxygen concentrations (high oxygen) (1). The use of intermittent positive-pressure ventilation was critical to the development of BPD because it provedto be a more effective artificial ventilation technique for small, severely ill, pre-mature infants than negative-pressure ventilation and could keep these infantsalive long enough to develop chronic lung disease. The prolongation of the usualclinical course of RDS for these moribund infants was dramatic as was the radio-graphic appearance of chronic lung disease.

6 Northway

A. Pathogenesis

High concentrations of supplemental oxygen were used initially with the hopethat the oxygenation of these infants with RDS could be rapidly improved andthe oxygen concentration rapidly decreased before pulmonary oxygen toxicityoccurred. Unfortunately, this did not happen. Nine of the 13 infants treated withhigh oxygen concentrations for longer than 150 hr lived beyond 2 weeks of ageand all demonstrated BPD; 5 died and 4 survived with BPD. Nine of the 19infants treated for less than 150 hr with high oxygen concentrations survived andnone had BPD. The initial data suggested that the etiology of BPD was relatedto pulmonary oxygen toxicity.

B. Radiology

The radiographic progression to chronic lung disease was originally divided intofour stages (1). Stage I (23 days) (Fig. 2) was a period that clinically resembledacute RDS. All the infants reported had RDS as the cause of their respiratory

Figure 2 Chest radiograph of an infant from the original report of BPD with fine bilat-eral granularity and air bronchogram in the lungs characteristic of stage I disease. (FromRef. 1.)


failure. The early radiographic picture was indistinguishable from classic RDS.Stage II (410 days) had a chest radiograph that, in the severest cases, showednearly complete opacification of both lungs. Stage III (1020 days) was a periodof transition to chronic disease, when the chest radiograph changed to a strikingpicture of small rounded areas of lucency distributed throughout both lungs. StageIV (beyond 1 month) (Fig. 3) represented the beginning of chronic disease. Thedefinition of chronic lung disease as beginning at 1 month of age was arbitraryand not manifested by any specific radiographic or clinical change that occurredat that time, but has proved to be a useful diagnostic criterion. Chest radiographsat this stage showed enlargement of the rounded lucent areas in the lungs thatalternated with strands of radiodensity. The lungs were hyperexpanded and car-diomegaly could be present.

C. Pathology

The initial stage I pathological appearance of BPD reflected the pathology ofthe predisposing cause of respiratory failureRDS with hyaline membranes andatelectasis. There was also patchy loss of ciliated cells, with metaplasia and necro-

Figure 3 Chest radiograph of an infant from the original report of BPD with stage IVdisease and persistence of irregular strands of density in the lungs, hyperexpansion, andcardiomegaly. (From Ref. 1.)

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sis of the bronchiolar mucosa (1). During stage II, when the infants were usuallyweaned from the respirator, but might still be receiving high oxygen concentra-tions, histological examination showed necrosis and repair of alveolar epithelium,with emphysematous coalescence of alveoli; increased patchy bronchiolar necro-sis, with patchy squamous metaplasia; and focal thickening of the capillary base-ment membranes. During stage III, the transition to chronic disease, there waswidespread bronchial and bronchiolar mucosal metaplasia and hyperplasia andmarked secretion of mucous and alveolar coalescence progressing to sphericallycircumscribed groups of emphysematous alveoli with atelectasis of surroundingalveoli. It was this pathological process that gave the chest radiograph its charac-teristic appearance with focal areas of radiolucency and radiodense stranding.In addition there was interstitial edema and focal thickening of the basementmembranes and some interseptal collagen deposition. By stage IV, there wasmarked hypertrophy of peribronchiolar smooth muscle, with focally circum-scribed groups of emphysematous alveoli and atelectatic alveolar areas. Therewas focal thickening of basement membranes, with separation of capillaries fromalveolar epithelium. Vascular lesions of the pulmonary hypertensive type wereseen, as well as marked heterotopia of alveolar epithelial cell types and wide-spread metaplasia of bronchiolar mucosa. Right-sided cardiomegaly might alsobe present. The progressive pathological changes in the immature lung affectedboth the parenchyma and airways and appeared to alter normal lung growth,suggesting the descriptive name bronchopulmonary dysplasia.

IV. The Evolution of BPD

Since its original description, BPD has been seen throughout the world whenever mechanical ventilation and supplemental oxygen therapy are used to treatprematurely born infants with respiratory failure. It is now as common as cysticfibrosis as a cause of chronic lung disease in children in the United States (36).Bronchopulmonary dysplasia clinics have been developed in many medical cen-ters. Home care of patients with BPD is increasingly important (37,38). Parentsupport groups have been organized. The cost of care for patients with BPDboth in and out of the hospital has become of concern (39). Bronchopulmonarydysplasia, however, is not only a clinical problem for neonatologists and pediatri-cians, but also for internists and general practitioners because it is now recognizedthat its sequelae may continue to affect the patient as an adult. UnderstandingBPD as it has evolved is basic to its future prevention and treatment.

A. Pathogenesis

The pathogenesis of BPD is now believed to be multifactorial. The four majoretiologic factors are (1) respiratory failure, (2) lung immaturity, (3) pulmonary


oxygen toxicity, and (4) volutrauma. Bronchopulmonary dysplasia can be bestunderstood as an injury and repair process occurring in the immature lung second-ary to pulmonary oxygen toxicity and pressure-induced trauma. The injury andrepair process throughout its course may be mild, moderate, severe, or very severe(40). The clinical manifestations of BPD depend on the immaturity of the devel-oping lung, the concentration of the supplemental oxygen, the level of airwaypressure, and the duration of exposure to the oxygen and pressure.

Although BPD was originally described in infants with RDS, it is nowrecognized that treatment of respiratory failure from many causes, such as meco-nium aspiration pneumonia (41), neonatal pneumonia (42), congestive heart fail-ure (43), the WilsonMikity syndrome (44), congenital diaphragmatic hernia(45), and marked degrees of prematurity with inadequate respiratory drive, canlead to BPD (46,47). Respiratory failure is critical to the pathogenesis of BPDbecause it requires treatment with supplemental oxygen and mechanical ventila-tion. Although pulmonary air leaks (pulmonary interstitial emphysema, pneu-momediastinum, pneumothorax) (48), pulmonary edema (49), and pulmonary in-fection (50,52) are associated with an increased incidence of BPD, none of thesefactors have been shown to be essential to its development. Presumably thesefactors increase the risk of developing BPD by prolonging the need for mechani-cal ventilation and supplemental oxygen therapy.

The relation of the duration of high-concentration oxygen therapy to thedevelopment of BPD in the original population of infants with RDS stronglysuggested that the etiology was related to pulmonary oxygen toxicity (1). Subse-quent exposure of newborn guinea pigs to 95100% oxygen produced pathologi-cal and radiographic changes in their lungs similar to the appearance of stage IIBPD. These studies demonstrated, for the first time, that pulmonary oxygen toxic-ity could produce chest radiographic changes in a newborn animal model (52).Experiments with newborn C-57 black mice continuously exposed to 90100%oxygen for up to 6 weeks produced a chronic lung disease that resembled allaspects of the pathology seen in human prematurely born infants with BPD (53).Tritiated thymidine uptake in these newborn mice demonstrated an inhibition ofDNA synthesisalteration in lung growthrelative to air-exposed controllednewborn mice (54), lending credence to the use of the term dysplasia in broncho-pulmonary dysplasia. We now know that most newborn animals are relativelytolerant to hyperoxia compared with the adult of the same species (55). The abilityof a newborn animal and probably the human newborn infant to survive a hyper-oxic challenge that would kill an adult animal is related to its ability to increaseits pulmonary antioxidant enzyme level in a hyperoxic environment, to producefewer oxygen free radicals intracellularly, to have less inflammatory cell influx,to have fewer mature inflammatory cells with less effective oxidative bursts, togenerate less inflammatory intermediaries, to have increased intracellular levelsof polyunsaturated fatty acids (free oxygen radical scavengers), and to maintain

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cell proliferation when challenged by a hyperoxic exposure, to a greater extentthan the adult animal (56). These features of the newborn animal response tooxygen injury in the lung are not present in the adult animal or human and maybe reduced in the prematurely born human infant. The development of a BPD-like picture in the prematurely delivered primate or mammal requires both thepresence of supplemental oxygen and mechanical ventilation; otherwise, the pre-maturely delivered animal will not survive long enough to develop BPD (57).As a result neither pressure-induced trauma nor pulmonary oxygen toxicity alonehas been shown in any prematurely delivered animal model to produce the fullrange of pathology seen in BPD in the immature human infant. The level ofoxygen concentration and peak ventilator pressure that is noninjurious to the veryimmature developing lung is unknown.

B. RDS Mortality

Improvements in management of the endotracheal tube, pulmonary toilet, themaintenance of the nutrition of the premature infant, accurate micromeasurementof blood gas tensions, establishment of normal physiological blood gas valuesfor prematurely born infants in the first few hours of life, administration of moreaccurately measured concentrations of supplemental oxygen (58), improvementsin the techniques of mechanical ventilation, including use of positive end-expira-tory pressure (59), continuous positive-airway pressure (60), various types of jetventilation, and the use of human and artificial surfactant, have resulted in areduction in the mortality from RDS so that it is no longer the leading cause ofdeath in live-born premature infants (61). Not only has the mortality from RDSdecreased, but there have been significant modifications in BPD. These includea general decrease in the severity of the radiologic picture and changes in itsepidemiology.

C. Incidence of BPD

With improvements in neonatal care and reduction in the use of high concentra-tions of oxygen and peak airway pressures, there has been a decrease in theincidence of BPD in the birth weight group who are heavier than 1500 g. Theoverall incidence in infants with RDS appears to have risen since 19621965,whereas the inhospital mortality for BPD has decreased. The overall incidencemay have risen because there has been a concomitant increase in survival of verylow birth weight infants (1000 g) with BPD (62). In 19621965 intensive caretechniques that would allow prolonged mechanical ventilation of these very lowbirthweight infants had not been developed. Infants as small as 280 g birthweightare now being successfully mechanically ventilated to survive (63). However, itis these very low birthweight infants that currently have the highest incidence ofBPD and pose the greatest challenge to reducing its incidence (64).


D. Radiology

Modification of the original four-stage radiographic picture of development ofBPD has accompanied the changes in birthweight-specific incidence of BPD.These modifications are related to the mechanical ventilation of increasingly im-mature infants, utilization of lower concentrations of supplemental oxygen, andlower peak ventilator pressures. As a result the chest radiographic picture is usu-ally less severe than originally described. Radiographic stage II, with completeopacification of both lungs, is seen infrequently. Radiographic stage IV diseaseor the chronic lung disease stage, with rounded lucencies and coarse radiodensestranding is still seen in the most severe cases, but more frequently there is afine reticular increase in lung density that is prolonged beyond 28 days of age.In some cases, the lungs may only remain persistently hazy with some degreeof hyperexpansion later than 28 days of age (65). The chronicity of these radio-graphic findings aids in establishing the diagnosis of BPD.

E. Diagnosis

As a result of these changes in the epidemiology and the radiographic picture ofBPD, revised diagnostic criteria have been developed (66). The Bureau of Mater-nal and Child Health and Resources Development has put forward the followingdiagnostic criteria:

1. Positive-pressure ventilation during the first 2 weeks of life for a mini-mum of 3 days.

2. Clinical signs of respiratory compromise persisting beyond 28 days ofage.

3. Requirement for supplemental oxygen longer than 28 days of age tomaintain a Pao2 higher than 50 mmHg.

4. Chest radiograph with findings characteristic of BPD.

The use of mechanical ventilation is still considered a prerequisite for de-velopment of BPD even though BPD has been reported to have developed in aninfant who was ventilated with only an Ambubag (67). Persistent respiratorydistress requiring oxygen supplementation to maintain a Pao2 above 50 mmHgestablishes the presence of lung disease beyond 28 days. The modified radio-graphic criteria allows for the changes from the original radiographic picture (68).

The clinical diagnosis of BPD remains difficult before 34 weeks of post-natal age. Tracheal aspiration with cytological analysis and radiologic correlationmay provide earlier diagnosis (69). Biochemical analysis of bronchoalveolar la-vage fluid has shed interesting information on the inflammatory response of thelung developing BPD (7072), but has not yet been particularly useful clinicallyin establishing early diagnosis. It is unclear that early measurement of pulmonarymechanics will be helpful for prediction of infants at risk for BPD (73,74). Post-

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poning the diagnosis to the equivalent of 36 weeks gestational age has been advo-cated as possibly providing a more useful prognosis relative to persistence ofchronic lung disease, but the usefulness of this modification of diagnosis is stillunclear (75). Toce and Edwards have developed a clinicalradiographic scoringsystem for judging the severity of BPD (76), and a new radiographic scoringsystem has been also been devised (77). The usefulness of these scoring systemsin measuring the severity of BPD and providing prognostic information and mea-suring treatment efficiency is unclear.

F. Terminology

As a result of the changes in epidemiology and radiology of BPD, there has beenincreased use of the term chronic lung disease of prematurity to describe eitherthe less severe form of BPD or the complete spectrum of BPD including the mostsevere form originally described (78). Regardless of the terminology, infants whodie with chronic lung disease of prematurity or chronic lung disease of earlyinfancy have the pathology of BPD (59).

G. Follow-Up

The surviving 1- to 2-year-old infants with BPD have persistent pulmonary dys-function, including increased airways resistance, increased airway reactivity, lowdynamic compliance, increased functional residual capacity, increased respiratoryrate, high arterial carbon dioxide tension, low arterial oxygen tension, severemaldistribution of ventilation, right and sometimes left ventricular hypertrophy,pulmonary hypertension, and systemic hypertension (7988). These abnormali-ties may improve, but do not necessarily resolve with age (8991).

There is little information available on the histopathology of the lungs ofolder infants and young children who have previously had BPD. Margraf de-scribed the histopathology of the lung in a series of eight infants dying withpersistent BPD (92). The oldest of these infants died 28 months after birth. Thereis one case report of an infant who died 34 months after birth, and this reportincluded a description of the morphology and morphometry of the lungs (93).Both morphometric studies revealed that older infants with previous BPD had adecrease in the total alveolar number and internal alveolar surface area relativeto control normal values. The study by Margraf showed an increase in bronchialsmooth muscle and glands, and a decrease in bronchiolar diameter, with bronchio-lar smooth-muscle hypertrophy in the patients with BPD. Children who undergolung transplantation for persistent, severe BPD could provide additional informa-tion concerning the late pathological sequelae of this condition.

Although histopathological evidence of persistent lung damage is currentlynot available from children with BPD who are older than 34 months of age,persistent pulmonary dysfunction in older children and young adults with previ-


ous BPD has been demonstrated. Increased lung volumes, airway obstruction,and increased transcutaneous carbon dioxide tensions have been documented ina group of ten children with an average age of 10.5 years who had prior BPD(94). Other investigators have found persistent pulmonary dysfunction in infantswith more recently diagnosed BPD (95) and in older children with BPD (90).The pulmonary dysfunction demonstrated in infants and in children with priorBPD often improves over time (90,91). Smythe noted increased airways resis-tance, air trapping, and blood gas and electrocardiographic abnormalities in ninepatients with BPD with an average age of approximately 10 years (96). Methacho-line challenge in these patients indicated the presence of persistent reactive air-ways disease.

Seventy-six percent of 25 young adults with prior BPD (mean age 18.3years) showed increased airways resistance, air trapping, and increased reactiveairways disease compared with a cohort of individuals who were matched forbirth weight and a group of normal adults who were born at term gestation (97).Only 6 of these young adults had severe pulmonary dysfunction and only 6 suf-fered respiratory symptoms. Other investigators have reported similar late pulmo-nary dysfunction in young adults with previous BPD (98). It appears that manychildren and young adults with prior BPD can be expected to have some persistentpulmonary function abnormalities, but in most of these there are no symptomsof residual lung disease.

The chest radiograph of children with prior BPD tends to improve slowlyover time and has been said to be normal by 23 years of age (99). However,permanent changes of BPD on chest radiographs may be seen in older childrenand young adults. These changes are typically subtle and consist primarily ofperibronchial cuffing, focal and diffuse linear densities, hyperexpansion, pleuralscarring, and occasional pectus carinatum or excavatum deformities (97,100).High-resolution computed tomography (CT) scans of the lungs of children andyoung adults with prior BPD can demonstrate septal thickening, areas of focalincreased lucency that may represent either persistent emphysema or focal areasof air trapping, and vascular remodeling (101,102).

The persistent pulmonary dysfunction and radiographic changes seen inchildren and young adults with prior BPD may represent not only the sequelaeof prior BPD but may also be related to intercurrent infection. Infants and childrenwith BPD appear to have an increased risk of respiratory syncytial virus pneumo-nia (103) and greater severity of infection (104).

The persistent pulmonary dysfunction seen in infants and young childrenwith more recently diagnosed BPD indicates that the radiographic and pulmonarydysfunction changes seen in young adults with prior BPD still occurs, even withthe intervening improvements in neonatal intensive care. Although the use ofhigh concentrations of oxygen and peak ventilator pressures has decreased since19621965, supplemental oxygen and mechanical ventilation with increased air-

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way pressure has been used to treat an increasingly immature lung and one thatis possibly more susceptible to oxygen injury (56). Surfactant therapy, althoughcorrecting the surfactant deficiency, should not be expected to accelerate the ana-tomical maturity of the lung or the maturity of the antioxidant system.

Bronchopulmonary dysplasia or chronic lung disease of early infancy isunlikely to decrease in incidence or disappear until premature birth, respiratoryfailure in the newborn infant, pulmonary oxygen toxicity, and pressure-inducedtrauma are better understood and are prevented or more successfully treated.

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