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LUNG SURFACTANT FUNCTION AND DISORDER

LUNG BIOLOGY IN HEALTH AND DISEASE

Executive Editor

Claude Lenfant

Former Director, National Heart, Lung, and Blood Institute

National Institutes of Health Bethesda, Maryland

1 Immunologic and Infectious Reactions in the Lung,

edited by C H Kirkpatrick and H Y Reynolds

2 The Biochemical Basis of Pulmonary Function, edited by

R G Crystal

3 Bioengineering Aspects of the Lung, edited by J B West

4 Metabolic Functions of the Lung, edited by Y S Bakhle

and J R Vane

5 Respiratory Defense Mechanisms (in two parts), edited by

J D Brain, D F Proctor, and L M Reid

6 Development of the Lung, edited by W A Hodson

7 Lung Water and Solute Exchange, edited by N C Staub

8 Extrapulmonary Manifestations of Respiratory Disease,

edited by E D Robin

9 Chronic Obstructive Pulmonary Disease, edited by T L Petty

10 Pathogenesis and Therapy of Lung Cancer, edited by

C C Harris

11 Genetic Determinants of Pulmonary Disease, edited by

S D Litwin

12 The Lung in the Transition Between Health and Disease,

edited by P T Macklem and S Permutt

13 Evolution of Respiratory Processes: A Comparative Approach,

edited by S C Wood and C Lenfant

14 Pulmonary Vascular Diseases, edited by K M Moser

15 Physiology and Pharmacology of the Airways, edited by

J A Nadel

16 Diagnostic Techniques in Pulmonary Disease (in two parts),

edited by M A Sackner

17 Regulation of Breathing (in two parts), edited by T F Hornbein

18 Occupational Lung Diseases: Research Approaches

and Methods, edited by H Weill and M Turner-Warwick

19 Immunopharmacology of the Lung, edited by H H Newball

20 Sarcoidosis and Other Granulomatous Diseases of the Lung,

edited by B L Fanburg

21 Sleep and Breathing, edited by N A Saunders

and C E Sullivan

22 Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L S Young

23 Pulmonary Nuclear Medicine: Techniques in Diagnosis of

Lung Disease, edited by H L Atkins

24 Acute Respiratory Failure, edited by W M Zapol

and K J Falke

25 Gas Mixing and Distribution in the Lung, edited by L A Engel

and M Paiva

26 High-Frequency Ventilation in Intensive Care and During

Surgery, edited by G Carlon and W S Howland

27 Pulmonary Development: Transition from Intrauterine to

Extrauterine Life, edited by G H Nelson

28 Chronic Obstructive Pulmonary Disease: Second Edition,

edited by T L Petty

29 The Thorax (in two parts), edited by C Roussos

and P T Macklem

30 The Pleura in Health and Disease, edited by J Chrétien,

J Bignon, and A Hirsch

31 Drug Therapy for Asthma: Research and Clinical Practice,

edited by J W Jenne and S Murphy

32 Pulmonary Endothelium in Health and Disease, edited by

U S Ryan

33 The Airways: Neural Control in Health and Disease,

edited by M A Kaliner and P J Barnes

34 Pathophysiology and Treatment of Inhalation Injuries,

edited by J Loke

35 Respiratory Function of the Upper Airway, edited by

O P Mathew and G Sant’Ambrogio

36 Chronic Obstructive Pulmonary Disease: A Behavioral

Perspective, edited by A J McSweeny and I Grant

37 Biology of Lung Cancer: Diagnosis and Treatment, edited by

S T Rosen, J L Mulshine, F Cuttitta, and P G Abrams

38 Pulmonary Vascular Physiology and Pathophysiology,

edited by E K Weir and J T Reeves

39 Comparative Pulmonary Physiology: Current Concepts,

edited by S C Wood

40 Respiratory Physiology: An Analytical Approach,

edited by H K Chang and M Paiva

41 Lung Cell Biology, edited by D Massaro

42 Heart–Lung Interactions in Health and Disease,

edited by S M Scharf and S S Cassidy

43 Clinical Epidemiology of Chronic Obstructive Pulmonary

Disease, edited by M J Hensley and N A Saunders

44 Surgical Pathology of Lung Neoplasms, edited by

A M Marchevsky

45 The Lung in Rheumatic Diseases, edited by G W Cannon

and G A Zimmerman

46 Diagnostic Imaging of the Lung, edited by C E Putman

47 Models of Lung Disease: Microscopy and Structural Methods,

edited by J Gil

48 Electron Microscopy of the Lung, edited by D E Schraufnagel

49 Asthma: Its Pathology and Treatment, edited by M A Kaliner,

P J Barnes, and C G A Persson

50 Acute Respiratory Failure: Second Edition, edited by

W M Zapol and F Lemaire

51 Lung Disease in the Tropics, edited by O P Sharma

52 Exercise: Pulmonary Physiology and Pathophysiology,

edited by B J Whipp and K Wasserman

53 Developmental Neurobiology of Breathing, edited by

G G Haddad and J P Farber

54 Mediators of Pulmonary Inflammation, edited by M A Bray

and W H Anderson

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

56 Physiological Adaptations in Vertebrates: Respiration,

Circulation, and Metabolism, edited by S C Wood,

R E Weber, A R Hargens, and R W Millard

57 The Bronchial Circulation, edited by J Butler

58 Lung Cancer Differentiation: Implications for Diagnosis

and Treatment, edited by S D Bernal and P J Hesketh

59 Pulmonary Complications of Systemic Disease, edited by

J F Murray

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

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 Genetics of Asthma, edited by S B Liggett

and D A Meyers

97 Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical

Actions, edited by R P Schleimer, W W Busse,

100 Lung Growth and Development, edited by J A McDonald

101 Parasitic Lung Diseases, edited by A A F Mahmoud

102 Lung Macrophages and Dendritic Cells in Health and Disease,

edited by M F Lipscomb and S W Russell

103 Pulmonary and Cardiac Imaging, edited by C Chiles

and C E Putman

104 Gene Therapy for Diseases of the Lung, edited by

K L Brigham

105 Oxygen, Gene Expression, and Cellular Function, edited by

L Biadasz Clerch and D J Massaro

106 Beta2-Agonists in Asthma Treatment, edited by R Pauwels

and P M O’Byrne

107 Inhalation Delivery of Therapeutic Peptides and Proteins,

edited by A L Adjei and P K Gupta

108 Asthma in the Elderly, edited by R A Barbee and J W Bloom

109 Treatment of the Hospitalized Cystic Fibrosis Patient,

edited by D M Orenstein and R C Stern

110 Asthma and Immunological Diseases in Pregnancy and Early

Infancy, edited by M Schatz, R S Zeiger, and H N Claman

111 Dyspnea, edited by D A Mahler

112 Proinflammatory and Antiinflammatory Peptides, edited by

S I Said

113 Self-Management of Asthma, edited by H Kotses

and A Harver

114 Eicosanoids, Aspirin, and Asthma, edited by A Szczeklik,

R J Gryglewski, and J R Vane

115 Fatal Asthma, edited by A L Sheffer

116 Pulmonary Edema, edited by M A Matthay and D H Ingbar

117 Inflammatory Mechanisms in Asthma, edited by S T Holgate

and W W Busse

118 Physiological Basis of Ventilatory Support, edited by

J J Marini and A S Slutsky

119 Human Immunodeficiency Virus and the Lung, edited by

M J Rosen and J M Beck

120 Five-Lipoxygenase Products in Asthma, edited by

J M Drazen, S.-E Dahlén, and T H Lee

121 Complexity in Structure and Function of the Lung, edited by

M P Hlastala and H T Robertson

122 Biology of Lung Cancer, edited by M A Kane

and P A Bunn, Jr.

123 Rhinitis: Mechanisms and Management, edited by

R M Naclerio, S R Durham, and N Mygind

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

130 Exercise-Induced Asthma, edited by E R McFadden, Jr

131 LAM and Other Diseases Characterized by Smooth Muscle

Proliferation, edited by J Moss

132 The Lung at Depth, edited by C E G Lundgren

and J N Miller

133 Regulation of Sleep and Circadian Rhythms, edited by

F W Turek and P C Zee

134 Anticholinergic Agents in the Upper and Lower Airways,

edited by S L Spector

135 Control of Breathing in Health and Disease, edited by

M D Altose and Y Kawakami

136 Immunotherapy in Asthma, edited by J Bousquet

and H Yssel

137 Chronic Lung Disease in Early Infancy, edited by R D Bland

and J J Coalson

138 Asthma’s Impact on Society: The Social and Economic

Burden, edited by K B Weiss, A S Buist, and S D Sullivan

139 New and Exploratory Therapeutic Agents for Asthma,

edited by M Yeadon and Z Diamant

140 Multimodality Treatment of Lung Cancer, edited by

A T Skarin

141 Cytokines in Pulmonary Disease: Infection and Inflammation,

edited by S Nelson and T R Martin

142 Diagnostic Pulmonary Pathology, edited by P T Cagle

143 Particle–Lung Interactions, edited by P Gehr and J Heyder

144 Tuberculosis: A Comprehensive International Approach,

Second Edition, Revised and Expanded, edited by

L B Reichman and E S Hershfield

145 Combination Therapy for Asthma and Chronic Obstructive

Pulmonary Disease, edited by R J Martin and M Kraft

146 Sleep Apnea: Implications in Cardiovascular

and Cerebrovascular Disease, edited by T D Bradley

and J S Floras

147 Sleep and Breathing in Children: A Developmental Approach,

edited by G M Loughlin, J L Carroll, and C L Marcus

148 Pulmonary and Peripheral Gas Exchange in Health

and Disease, edited by J Roca, R Rodriguez-Roisen,

and P D Wagner

149 Lung Surfactants: Basic Science and Clinical Applications,

R H Notter

150 Nosocomial Pneumonia, edited by W R Jarvis

151 Fetal Origins of Cardiovascular and Lung Disease, edited by

David J P Barker

152 Long-Term Mechanical Ventilation, edited by N S Hill

153 Environmental Asthma, edited by R K Bush

154 Asthma and Respiratory Infections, edited by D P Skoner

155 Airway Remodeling, edited by P H Howarth, J W Wilson,

J Bousquet, S Rak, and R A Pauwels

156 Genetic Models in Cardiorespiratory Biology, edited by

G G Haddad and T Xu

157 Respiratory-Circulatory Interactions in Health and Disease,

edited by S M Scharf, M R Pinsky, and S Magder

158 Ventilator Management Strategies for Critical Care, edited by

N S Hill and M M Levy

159 Severe Asthma: Pathogenesis and Clinical Management,

Second Edition, Revised and Expanded, edited by

S J Szefler and D Y M Leung

160 Gravity and the Lung: Lessons from Microgravity, edited by

G K Prisk, M Paiva, and J B West

161 High Altitude: An Exploration of Human Adaptation, edited by

T F Hornbein and R B Schoene

162 Drug Delivery to the Lung, edited by H Bisgaard,

C O’Callaghan, and G C Smaldone

163 Inhaled Steroids in Asthma: Optimizing Effects in the Airways,

edited by R P Schleimer, P M O’Byrne, S J Szefler, and R Brattsand

164 IgE and Anti-IgE Therapy in Asthma and Allergic Disease,

edited by R B Fick, Jr., and P M Jardieu

165 Clinical Management of Chronic Obstructive Pulmonary

Disease, edited by T Similowski, W A Whitelaw,

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 Infections in Allergy and Asthma, edited by

S L Johnston and N G Papadopoulos

179 Acute Respiratory Distress Syndrome, edited by

M A Matthay

180 Venous Thromboembolism, edited by J E Dalen

181 Upper and Lower Respiratory Disease, edited by J Corren,

A Togias, and J Bousquet

182 Pharmacotherapy in Chronic Obstructive Pulmonary Disease,

edited by B R Celli

183 Acute Exacerbations of Chronic Obstructive Pulmonary

Disease, edited by N M Siafakas, N R Anthonisen,

and D Georgopoulos

184 Lung Volume Reduction Surgery for Emphysema, edited by

H E Fessler, J J Reilly, Jr., and D J Sugarbaker

185 Idiopathic Pulmonary Fibrosis, edited by J P Lynch III

186 Pleural Disease, edited by D Bouros

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 Finkelstein, and Bruce Holm

197 Ion Channels in the Pulmonary Vasculature,

edited by Jason X.-J Yuan

198 Chronic Obstuctive Pulmonary Disease: Cellular and

Molecular Mechanisms, edited by Peter J Barnes

199 Pediatric Nasal and Sinus Disorders, edited by Tania Sih

and Peter A R Clement

200 Functional Lung Imaging, edited by David Lipson

and Edwin van Beek

201 Lung Surfactant Function and Disorder, edited by Kaushik Nag

202 Pharmacology and Pathophysiology of the Control

of Breathing, edited by Denham S Ward, Albert Dahan

and Luc J Teppema

203 Molecular Imaging of the Lungs, edited by Daniel Schuster

and Timothy Blackwell

204 Air Pollutants and the Respiratory Tract: Second Edition,

edited by W Michael Foster and Daniel L Costa

205 Acute and Chronic Cough, edited by Anthony E Redington

and Alyn H Morice

206 Severe Pneumonia, edited by Michael S Niederman

The opinions expressed in these volumes do not necessarily represent

the views of the National Institutes of Health.

Boca Raton London New York Singapore

Edited by

Kaushik Nag

Memorial University of Newfoundland

St John’s, Newfoundland and Labrador, Canada

LUNG SURFACTANT FUNCTION AND DISORDER

Published in 2005 by Taylor & Francis Group

6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742

© 2005 by Taylor & Francis Group, LLC

No claim to original U.S Government works Printed in the United States of America on acid-free paper

10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8247-5792-0 (Hardcover) International Standard Book Number-13: 978-0-8247-5792-2 (Hardcover) This book contains information obtained from authentic and highly regarded sources Reprinted material is quoted with permission, and sources are indicated A wide variety of references are listed Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use.

No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400 CCC is a not-for-profit organization that provides licenses and registration for a variety of users For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged.

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DK3028_Discl Page 1 Friday, April 8, 2005 11:50 AM

Our odyssey of discovery and understanding with regard to lung surfactant hasbeen long and fascinating And indeed, the monographs found in the LungBiology in Health and Disease series has given recognition to this journeythrough chapters in several monographs and through entire volumes devoted tolung surfactant and its function in health and disease Some may ask the question

“Why is there such an interest in this subject?”

Two reasons can be found in two remarkable books In scope—Insight into Medical Discovery by Julius Comroe (1), the last three chap-ters titled “Premature Science and Immature Lungs, Part I to III” retrace thejourney of surfactant from Laplace’s Traite de Mecanique Celeste (2) to a life-saving treatment for prematurely born infants This journey spanned almosttwo centuries The second book, The Restless Tide—The Persistent Challenge ofthe Microbial World, by Richard M Krause (3) can be summed up in a quotationfrom Thomas Babington (1830): “A single breaker may recede; but the tide isevidently coming in.”

Retrospectro-The essential message of these two books—that, often, we think we knowwhat to do, but we really do not!—is actually the rationale for this new mono-graph Lung Surfactant Function and Disorder, edited by Dr Kaushik Nag.The reader is introduced to many disciplines applicable to the study of lung

iii

surfactant, including chemistry, biochemistry, physics, genetics, computerscience, physiology, and medicine All are presented by well-known investi-gators from many countries and several continents.

Overall, this book illustrates the complexity, and expectations, of research

on surfactant In his Preface, Dr Nag acknowledges Pierre De Gennes, whostated in his Nobel Lecture (1991) that “it is perhaps amazing to note thatthere is some overlap in thought between people who study high brow stringtheories, and description of soaps.” This is reminiscent of a statement by

C V Bogs in one of his lectures on “Soap Bubbles”: “I hope that none of youare yet tired of playing with bubbles because, as I hope we shall see, there ismore in a common bubble than those who have only played with them generallyimagine” (4)

The series Lung Biology in Health and Disease is very pleased to presentthis latest volume on surfactant It gives a new, and different perspective, remind-ing us that research and knowledge—like the tides—are a dynamic and an ever-renewed process

Claude Lenfant, MDGaithersburg, Maryland

There have been major breakthroughs in lung surfactant (LS) research over thelast two decades that have changed our concept of how and why the materialworks well at the lung air – water interface From the initial ideas of a surfaceactive material lining the alveoli to the seminal concepts of how low surfacetension is reached, the classical ideas about Comroe’s “extraordinary juice”requires revision and re-thinking From the early concepts developed by VonNeergard, Pattle, Clements, Avery, and Bangham—to current status and futuredirections developed by others—LS research has come a long way.

The concept of this volume was developed about two years ago, at a cal meeting and later at the American Thoracic Society meeting where I had thepleasure of meeting a number of upcoming researchers in the field I was humbled

Biophysi-to know how less a biophysicist like myself knew about the clinical and cular biology aspects of LS Our physicochemical way of looking at LS as amembranous or colloidal system was difficult to describe to the clinical scientists.This volume is a small contribution in explaining basic and clinical laboratoryknowledge to the larger audience and surfactant researchers, at an advancedbasic – clinical interface

mole-Although in recent years there have been a number of excellent reviews onvarious aspects of LS, like most reviews these tend to encompass a large volume

v

of data and multiple interpretations and do not allow for easily bringing in new cepts from researchers There are a number of other volumes included in the LungBiology in Health and Disease series, such as volumes 1, 12, 24, 35, 55, 84, 121,

con-143 that have chapters devoted to LS related research, and have contributed to ourunderstanding of LS over the last three decades There is also a single authoredvolume (vol 149), that focuses on biophysics as well as clinical aspects of LS at

a basic level There are also a few review books, almost a decade old, written

by experts in the field Normally, review books are written and edited by suchexperts However, breaking this norm for this volume was due to my personal situ-ation at the time of conception of this book as a post-doctoral fellow in an obscureuniversity in Canada At that time I was struggling with the toils and troubles ofstable bubbles, and of securing a more permanent position (possibly in anotherobscure university in Canada) I have enthusiastically pursued respiratory researchfrom my honors student days in India, leading to a masters in Physiology (Bio-physics) and Biochemistry, and finally doctoral and postdoctoral training in lungbiology Over the past two decades I have had the opportunity to observe the LSsystem from a biophysical as well as a clinical viewpoint During this periodwhat fascinated me about surfactant was that the molecular mechanisms of itsaction could be interpreted from fields as diverse as neonatal physiology, geneticknockout mice, soft condensed matter, and nanobiology

I had initially approached some new and upcoming researchers in this fieldwho were at this stage of transition—from postdoctoral to the higher echelons ofacademia—to either create their own chapter or do so with co-contributors Thisvolume is thus designed to focus on laboratory research areas of some newand exciting semi-classical concepts of LS that try to encompass biophysics,molecular biology, clinical physiology, developmental and microbiology aswell as surface and interfacial chemistry, physics, membranes, soft matter, andmolecular imaging The word “lung” is utilized throughout (and in the title) toreplace “pulmonary,” considering the presence of LS beyond the alveoli in theupper airways, and its role in asthma and upper respiratory tract disease Alsothe parenthesis to the word (dys)function is used since some of the functionalaspects of LS are not clear to date, and molecular mechanisms of disease anddysfunction of the material are only emerging

This book is structured in a format where we attempt to broadly discuss thediversity of molecular composition (Chapters 1 – 5) and some current method-ology in rapid analysis of LS lipids (Chapter 2) in various species and inhealth and disease (Chapter 1) The current status of surfactant proteins are pre-sented in Chapters 3, 4, and 5 A few surprises have emerged along the way, as wenow know that lung surfactant contain different disaturated lipids, other thanDPPC (Chapter 1), and that some species breathe fine without this lipid beingpresent in “large” amounts in their surfactant (Chapter 2) Others have recentlycompressed a fluid phospholipid film to reach near zero surface tensions incaptive bubbles (Chapter 6) and observed similar properties of liquid crystallinemembranes and LS (Chapter 7) The structure – function property of LS is too vast

and detailed, thus I have taken the liberty to select a set of discussions on thefunction of lipids and lipid – protein systems, from a molecular mechanism andbiophysics viewpoint (Chapters 6 – 13) Some of these (Chapters 9 – 13) discussthe classical concepts of the “laboratory assigned” roles of the surfactant proteinsfrom SP-A to SP-D, while we wait for SP-Es and Fs to emerge The book,however, includes other discussions especially for the possible new and emergingrole of hydrophobic proteins in processes such as channel activity (Chapters 8and 14) and in another section as antimicrobials (Chapter 17).

Although the final section of the book deals with (dys)function and diseaseaspects of surfactant from the clinical (Chapters 16 and 17), physiology (Chapter15), replacement therapy aspects (Chapter 19), only a few contributions areassembled to provide a sample of such studies (Chapters 15 – 19) This is due

to various aspects of lung disease related to LS discussed in previous booksand volumes of this series Thus I have only chosen a sample few, in order toprovide researchers the necessary laboratory experience I make no naiveclaims to either comprehend this vast area of respiratory distress, nor have Itried to attempt to provide a comprehensive and all inclusive glimpse at the com-plexity of LS dysfunction My sincerest apologies to numerous upcoming andexcellent researchers in this area for not being able include their work, due toshortage of textual space This will possibly also allow one to avoid extremephysical discomfort and consumption of muscle (brain) relaxants which may

be required while handling this volume A future volume in editorial ations with experts in the clinical areas may be forthcoming, depending on thereception of this volume by the LS community

collabor-I must confess my personal heavy-handedness in dealing with the ics section (Chapters 6 – 14) since this is one area I feel comfortable with com-pared to my naivety in most others (After all how do we study a floatingmembrane in the lung?) This section deals with the concept of low surfacetension in the lung that may be induced by a fluid lipid defying some classicalconcepts (Chapter 7), to applying cell membrane “lipid rafts” or structuralconcept to surfactant (Chapter 6) Such methods rely heavily on new and power-ful physicochemical techniques utilized to pin down single molecules, molecularmotions, and aggressively define LS as soft matter—either inside an atomic forcemicroscope (Chapters 11 and 12) or a computer (Chapter 9) Some of thismethodology also requires a certain level of mathematical sophistication to bedefined by experts (some of these colleagues are clinical scientists with doc-torates in physical chemistry and physics) Someday these technologies may behelpful to new and emerging researchers who venture into the intricate world

Biophys-of nuclear spins Biophys-of surfactant proteins (Chapter 11), knock-out genes (Chapter 13),and to smash DPPC under ion-beams (Chapter 10)

It would be a fallacy in even trying to acknowledge all the colleagues,co-authors, and experts that I have met and discussed LS research with for overtwo decades, having thus directly/indirectly contributed to this volume However,

I wish to thank a few, such as Dr Claude Lenfant (Executive Editor of this series)

for inviting me to edit this book, Prof Fereidoon Shahidi (Biochemistry, orial University), and Anita Lekhwani (Acquisitions Editor, Taylor & FrancisGroup), for help in providing the necessary enthusiasm, editorial, and publicationguidelines, without which this volume would never have seen publication Iwould be remiss not to acknowledge the help and support of my mentor Dr.Kevin Keough (President, Alberta Heritage Foundation for Medical Research,Canada), who has continuously and enthusiastically encouraged as well as criti-cized my continuous adventure into the world of LS and membranes A belatedgratitude goes to the late Prof Haripada Chattopadhayay of Presidency College,Kolkata (West Bengal, India) who had first showed me how breathing patterns ofhumans change due to circadian rhythms, in a dark room in India Incidentallythis room was above a floor of the Physics department, where C.V Raman and

Mem-S Bose extrapolated their ideas on molecular vibration patterns and Bose –Einstein condensates, more than half a century ago Funding for my studies inNorth America is gratefully acknowledged from the Medical Research Council

of Canada, Ontario Thoracic Society, Canadian Lung Association, NationalScientific and Educational Research Council, and recently from Canadian Insti-tute of Health Research, Canada Foundation for Innovation, and Memorial Uni-versity of Newfoundland

Having actually watched the whales spray their lung surfactant in the bays

of Newfoundland, to seeing and touching the terminal methyl chains of DPPC—

or observing neonatal recovery after LS administration—I feel there are manyfascinating discoveries yet to be made on Comroe’s “extraordinary juice.” Asthe master of analogy Pierre De Gennes stated in his Nobel Lecture “it isperhaps amusing to note that there is some overlap in thought between peoplewho study high brow string theories and description of soaps” (see Chapter 6for details) I sincerely hope this volume provides such overlap in lung surfactantresearchers from biology, chemistry, physics, computer science, and medicine

Kaushik Nag

Mathias Amrein Faculty of Medicine, University of Calgary, Alberta,Calgary, Canada

Rinti Banerjee School of Biosciences and Bioengineering, Indian Institute ofTechnology, Mumbai, India

Timothy C Bailey Department of Physiology and Pharmacology andDepartment of Medicine, University of Western Ontario, London, Ontario,Canada

Wolfgang Bernhard Division of Neonatology, University of Tu¨bingen,Tu¨bingen, Germany

Nikolaus Bourdos Institut fu¨r Biochemie, Westfa¨lische Wilhelms-Universita¨tMu¨nster, Mu¨nster, Germany

Current affiliation: Lehrstuhl fu¨r Biophysik, Ruhr Universita¨t Bochum, strasse, Bochum, Germany

Universita¨ts-ix

Cristina Casals Department of Biochemistry and Molecular Biology I,Complutense University of Madrid, Madrid, Spain

Antonio Cruz Department of Bioquı´mica, Universidad Complutense, Madrid,Spain

Christopher B Daniels Department of Environmental Biology, University ofAdelaide, Adelaide, Australia

Haim Diamant Department of Chemistry, Tel Aviv University, Tel Aviv, IsraelJonathan R Faulkner Departments of Ob/Gyn and Biochemistry, University

of Western Ontario, London, Ontario, Canada

Hans-Joachim Galla Institut fu¨r Biochemie, Westfa¨lische Universita¨t Mu¨nster, Mu¨nster, Germany

Wilhelms-Ignacio Garcı´a-Verdugo Department of Biochemistry and Molecular Biology

I, Complutense University of Madrid, Madrid, Spain

Donald P Gaver III Department of Biomedical Engineering, Tulane sity, New Orleans, Louisiana, USA

Univer-Stephan W Glasser Division of Pulmonary Biology, Cincinnati Children’sHospital Medical Center, Cincinnati, Ohio, USA

Stephen B Hall Molecular Medicine, Oregon Health & Science University,Portland, Oregon, USA

David Halpern Department of Mathematics, University of Alabama,Tuscaloosa, USA

Egbert Herting Professor of Pediatrics, University of Lu¨beck, Lu¨beck,Germany

Robert R Harbottle Department of Chemistry, University of WesternOntario, London, Ontario, Canada

Jens M Hohlfeld Department of Respiratory Medicine, Hannover MedicalSchool and Fraunhofer Institute of Toxicology and Experimental Medicine,Hannover, Germany

M G Haufs BGFA, Ruhr-Universita¨t Bochum, Bochum, Germany

Oliver E Jensen School of Mathematical Sciences, University ofNottingham, Nottingham, UK

Chutima Jiarpinitnun Department of Chemistry, The University of Chicago,Chicago, Illinois, USA

Yiannis N Kaznessis Department of Chemical Engineering andMaterials Science, and Digital Technology Center, University of Minnesota,Minneapolis/St Paul, Minnesota, USA

D Knebel JPK-Instruments AG, Berlin, Germany

Thomas R Korfhagen Division of Pulmonary Biology, Cincinnati Children’sHospital Medical Center, Cincinnati, Ohio, USA

Josh W Kurutz Department of Chemistry, The University of Chicago,Chicago, Illinois, USA

Carol J Lang Department of Environmental Biology, University of Adelaide,Adelaide, Australia

Ronald G Larson Department of Chemical Engineering, University ofMichigan, Ann Arbor, Michigan, USA

Stefan Malcharek Institut fu¨r Biochemie, Westfa¨lische Wilhelms-Universita¨tMu¨nster, Mu¨nster, Germany

Jeya Nadesalingam Department of Biochemistry, Oxford University,Oxford, UK

Kaushik Nag Department of Biochemistry, Memorial University of land, St John’s, Newfoundland and Labrador, Canada

Newfound-David G Oelberg Center for Pediatric Research, Eastern Virginia MedicalSchool and Children’s Hospital of The King’s Daughters, Norfolk, Virginia, USASandra Orgeig Department of Environmental Biology, University of Adelaide,Adelaide, Australia

Nades Palaniyar Department of Biochemistry, Oxford University,Oxford, UK

Amiya K Panda Department of Chemistry, Behala College, Kolkata,West Bengal, India

Jesu´s Pe´rez-Gil Department of Bioquı´mica, Universidad Complutense,Madrid, Spain

Ine´s Plasencia Department of Bioquı´mica, Universidad Complutense, Madrid,Spain

Fred Possmayer Departments of Ob/Gyn and Biochemistry, University ofWestern Ontario, London, Ontario, Canada

Current affiliation: Lung Biology Research Program, Hospital for Sick ChildrenResearch Institute, Toronto, Ontario, Canada

Tony Postle Division of Infection, Inflammation and Repair, School ofMedicine and Southampton General Hospital, Southampton, UK

Kenneth B M Reid Department of Biochemistry, Oxford University,Oxford, UK

Bengt Robertson Laboratory for Surfactant Research, Department ofSurgical Sciences, Karolinska University Hospital, Stockholm, Sweden

Karina Rodriguez-Capote Departments of Ob/Gyn and Biochemistry,University of Western Ontario, London, Ontario, Canada

Sandra Rugonyi Molecular Medicine, Oregon Health & Science University,Portland, Oregon, USA

Ruud A W Veldhuizen Department of Physiology and Pharmacology andDepartment of Medicine, University of Western Ontario, London, Ontario,Canada

Sangeetha Vidyashankar Department of Biochemistry, Memorial University

of Newfoundland, St John’s, Newfoundland and Labrador, Canada

Alan J Waring Department of Pediatrics, University of California, LosAngeles, California, USA

Tom Witten The James Franck Institute and Department of Physics, TheUniversity of Chicago, Chicago, Illinois, USA

Ka Yee C Lee The Institute for Biophysical Dynamics, The University ofChicago, Chicago, Illinois, USA

Introduction Claude Lenfant iiiPreface vContributors ix

COMPOSITION, STRUCTURE, AND FUNCTION

1 Lung Surfactant Phospholipid Molecular Species in

Health and Disease 3Tony Postle and Wolfgang Bernhard

I Introduction 3

II Composition of Surfactant Phospholipid Molecular

Species in the Adult Lungs 6

III Molecular Species of Surfactant Phospholipid During

Fetal Development 9

IV Molecular Species of Phospholipid During

Postnatal Development 9

V Modification of Surfactant Phospholipid Molecular

Species in Disease States 10

xiii

VI Conclusion 12

References 12

2 New Insights into the Thermal Dynamics of the Surfactant

System from Warm and Cold Animals 17Carol J Lang, Christopher B Daniels, and Sandra Orgeig

I Introduction 18

II Temperature and the Biophysical Properties of Surfactant 22III Temperature and Surfactant Composition 32

IV Temperature and Control of Surfactant Secretion 41

V Summary and Future Directions 49

References 49

3 Molecular and Functional Properties of Surfactant

Protein A 59Cristina Casals and Ignacio Garcı´a-Verdugo

I Introduction 59

II Structure/Function Relationship 62

III SP-A Functions 69

IV Concluding Remarks 77

Acknowledgment 78

References 78

4 Receptors and Ligands for Collectins Surfactant

Proteins A and D 87Nades Palaniyar, Jeya Nadesalingam, and

Kenneth B M Reid

I Introduction 88

II Collectins and Related Proteins 89

III Tissue Distribution of SP-A and SP-D 91

IV Potential Functions of SP-A and SP-D 91

V Structure of SP-A and SP-D 91

VI Ligands for SP-A and SP-D 93

VII Cells and Receptors 99

VIII Summary and Future Directions 109

Acknowledgments 110

References 110

5 Structure – Function Relationships of Hydrophobic

Proteins SP-B and SP-C in Pulmonary Surfactant 125Jesu´s Pe´rez-Gil, Antonio Cruz, and Ine´s Plasencia

I Introduction 125

II Evolutionary Origin of Hydrophobic Pulmonary

Surfactant Proteins 126

III Biological vs Clinical Engineering of

Pulmonary Surfactant 127

IV Structure – Function Relationships of SP-B 128

V Structure – Function Relationships of SP-C 132

Acknowledgments 136

References 136

BIOPHYSICS AND MOLECULAR MECHANISMS

6 Chain Dancing, Super-Cool Surfactant, and Heavy

Breathing: Membranes, Rafts, and Phase Transitions 145Kaushik Nag, Sangeetha Vidyashankar, Amiya K Panda,

and Robert R Harbottle

I Introduction 145

II Membranes, Rafts, and Lung Surfactant 148

III Chain Dancing 150

IV Nanotubes Revisited 152

V Physiological Correlates 154

VI Supercool Surfactant 156

VII The Cholesterol Mystery 159

VIII Heavy Breathing: Critical Behavior Disrupted 162

IX The Future 165

II Physiological Significance of Airway Lining Flows and

Surface Tension in the Lung 192

III Interfacial Phenomena 197

IV Physiological Interfacial Flows 201

V Conclusions 219

Acknowledgments 220

References 220

9 Lung Surfactants: A Molecular Perspective

from Computation 229Yiannis N Kaznessis and Ronald G Larson

I Introduction 229

II Simulations Methodology 233

III Simulation Results 235

IV Conclusions 245

References 245

10 Analysis of Surface Topology and Chemical

Composition of Microstructures Formed in Planar

Surfactant Films Under Compression 251Hans-Joachim Galla, Stefan Malcharek,

and Nikolaus Bourdos

I Introduction 252

II Topological Analysis of Domains Structures 255

III Chemical Analysis Surfactant Composition Using

Imaging Time-of-Flight Secondary Ion

Ka Yee C Lee, Haim Diamant, and Alan J Waring

I Introduction 275

II SP-B Surfactant Peptide Synthesis 277

III NMR Structure of SP-B Peptides 283

IV Effect of SP-B Peptides on LS Monolayer Collapse 288

V Elastic Theory of LS Monolayers 293

References 297

12 Structure and Function of the Molecular Film

of Pulmonary Surfactant at the Air – Alveolar Interface:

The Role of SP-C 301Mathias Amrein, D Knebel, and M G Haufs

13 Analysis of SP-C Function Using Transgenic and

Gene Targeted Mice 317Stephan W Glasser and Thomas R Korfhagen

I Introduction 317

II SP-C Structure and Function 318

III SP-C Gene Structure and Expression 319

IV SP-C Transgenes Identify Regions that Specify Pulmonary

Epithelial Cell Expression 319

V Altered Expression of SP-C and Familial ILD in Humans 322

VI SP-C Knockout Mice as a Model of ILD 323

VII Abnormalities in Surfactant Composition and Function with

SP-C Deficiency 325

VIII Utility of Current SP-C Mouse Models to Explore Pathogenic

Mechanisms and Therapy for Familial ILD 326

IV Clues from the Channel Activities of SAPLIPs 334

V Observed Cation Channel Insertion by SP-B/C in

Planar Lipid Bilayers 335

VI Observed Neutrophil Depolarization and G Protein-Mediated

Calcium Mobilization by Surfactant with SP-B/C 342

VII Observed Inhibition of Neutrophil Activation by

Surfactant with SP-B/C 345

VIII Conclusions 350

References 350

DYSFUNCTION AND DISEASE

15 The Physiological Significance of a Dysfunctional

Lung Surfactant 359Timothy C Bailey and Ruud A W Veldhuizen

I Introduction 359

II Physiological Function of Pulmonary Surfactant 360

III Surfactant Composition 362

IV Surfactant Metabolism 363

V Acute Lung Injury 363

VI Alterations of Surfactant During ALI 365

VII Mechanisms by Which Alterations of

Surfactant Occur 366

VIII Mechanisms by Which Alterations of Surfactant

Lead to a Loss in Function 368

IX Exogenous Surfactant Administration in ALI 368

X Conclusions and Future Directions 371

II General Aspects of Airway Surfactant 384

III Surfactant Alterations in Asthma 387

IV Modulation of Immune Cells in

II In Vitro Studies 400

III Animal Studies 407

IV Clinical Studies 409

V Summary and Perspectives 414

VI Conclusion 416

Acknowledgments 417

References 417

18 Alteration of Alveolar Surfactant Function by

Reactive Oxygen Species 425Karina Rodriguez-Capote, Jonathan R Faulkner,

Fred Possmayer, and Kaushik Nag

I Introduction 426

II Reactive Oxygen Species 427

III Antioxidant Defense Mechanisms 430

IV Biophysical and Biochemical Alterations of the Surfactant

System by ROS 433

V Summary 441

References 442

19 Novel Surfactant Therapy for Developing Countries:

Current Status and Future Directions 449Rinti Banerjee

IV In Vitro Evaluation of Surfactants 451

V Parameters of Physiological Relevance 451

VI In Vitro Results for Herbal Oil Surfactants

IX Surfactant Inhibition Studies In Vitro 456

X Tropical Causes of ARDS 458

XI Role of Airway Surfactant in Chronic Obstructive

Pulmonary Diseases 459

XII Rheological Properties of Airway Mucus 459

XIII Interaction of Surfactants with

Environmental Pollutants 461

XIV Surfactant System in Pulmonary Tuberculosis 463

XV Improved Delivery Forms of Lung Surfactant 465

XVI Issues of Toxicity of Herbal Oil Surfactants 466

XVII Summary 467

Acknowledgments 467

References 467

Index 471

Lung Surfactant Phospholipid Molecular Species in Health and Disease

II Composition of Surfactant Phospholipid Molecular Species in

III Molecular Species of Surfactant Phospholipid During Fetal

3

have received relatively little attention until recently, largely because of lack ofsensitivity and specificity of the analytical methods available Phospholipidsare characterized either as glycerophospholipids, with fatty acids esterified atthe sn-1 and sn-2 positions of the glycerophosphate backbone of the molecule,

or as sphingolipids, with a fatty acid esterified to a sphingosine phosphatemoiety (Fig 1.1) The head group attached to the phosphate of glycerophospho-lipids can be choline, ethanolamine, serine, glycerol, or inositol to give, respect-ively, phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn),phosphatidylserine (PtdSer), phosphatidylglycerol (PtdGly), or phosphatidyl-inositol (PtdIns) The vast majority of sphingolipids have choline esterified tothe phosphate to generate sphingomyelin Within each of these phospholipidclasses, there is a spectrum of individual molecular species, defined by the com-bination of esterified fatty acids attached to the glycerol Generally, membraneglycerophospholipids tend to have palmitoyl (16:0)1or stearoyl (18:0) at theirsn-1 position and unsaturated fatty acids esterified at sn-2 The esterified fattyacid in sphingolipids is generally saturated, but can often contain as many as

22 or 24 carbon atoms

Historically, techniques to measure individual molecular species of pholipids have been very time consuming and either insensitive or technicallydemanding An indication of the molecular species composition of surfactantphospholipid from newborn infants was provided by using thin-layer chromato-graphy on silver nitrate-impregnated silica plates (1), which resolves phospho-lipids on the basis of their total number of unsaturated double bonds More directinformation about individual species can be provided by high-performance liquidchromatography (HPLC), with either precolumn (2 – 4) or postcolumn (5,6)derivative formation, but these techniques have proved too specialized and labor-ious to be adopted for widespread use More recently, advances in instrumentdesign have established electrospray ionization-mass spectrometry (ESI-MS) as

phos-a technique for phos-anphos-alyzing phospholipid moleculphos-ar species in grephos-at detphos-ail phos-andwith exquisite sensitivity (7) ESI-MS is a soft ionization technique that generatesmolecular ions with minimal fragmentation and is ideally suited to characterizingsurfactant phospholipid molecular species (8,9)

Perhaps ironically, one additional reason for the relative lack of interest inindividual surfactant phospholipid molecular species was the early identification

of the importance of PC16:0/16:0 for surfactant function Demonstrations

1

The abbreviation for fatty acids is given by the number of carbon atoms and carbon:carbondouble bonds in the molecule Thus, the saturated 16 carbon atom palmitate molecule is16:0, the monounsaturated palmitoleate and oleate molecules are, respectively, 16:1 and18:1, and the more unsaturated linoleate and arachidonate molecules are, respectively,18:2 and 20:4 Individual molecular species of glycerophospholipids are designated first

by the identity of the polar headgroup and then by the combination of fatty acids.Consequently, dipalmitoyl phosphatidylcholine is PC16:0/16:0, whereas 1-stearoyl-2arachidonoyl phosphatidylinositol is PI18:0/20:4

in vitro that PC16:0/16:0 could mimic many of the surface properties of tant meant that little attention was paid in clinical studies to the precise identities

surfac-of the other phospholipid species In addition, development surfac-of simple robust niques to quantify disaturated PtdCho (DSPC) as the residue after the oxidativedestruction of unsaturated species (10) led to the general identification of DSPC

tech-as PC16:0/16:0 This concentration on the central importance of PC16:0/16:0 insurfactant function has been reinforced by more recent observations that an effec-tive exogenous surfactant can be constructed from this single PtdCho speciestogether with acidic phospholipids and hydrophilic surfactant peptides (11).However, considerable evidence now suggests that surfactant phospholipidcomposition varies in response to the physiological demands of breathing (12)and that PtdCho species other than PC16:0/16:0 may contribute to surfactantfunction This is especially relevant in the light of experiments showing thatmonounsaturated PtdCho species can display surface properties generallyattributed to PC16:0/16:0 (13) Moreover, recent studies have demonstratedthat under dynamic conditions surface tension lowering function of surfactants

is inferior for preparations which are highly enriched in PC16:0/16:0 but aredeprived in other characteristic PtdCho molecular species (discussed subsequently),irrespective of the presence of the hydrophobic surfactant protein SP-B (12)

OH O OFigure 1.1 Molecular structures of phospholipids

II Composition of Surfactant Phospholipid Molecular

Species in the Adult Lungs

Estimates that PC16:0/16:0 contributes 70 – 80% of surfactant PtdCho, based onthe OsO4oxidation technique, are now generally recognized as too high (14) bothbecause of the presence of other disaturated species including PC16:0/14:0 andPC16:0/18:0 and because of the oxidation of monounsaturated species is oftenincomplete In contrast, analysis by either HPLC or ESI-MS provides a goodagreement about the molecular species of PtdCho in lung surfactant, but thiscomposition can vary considerably between different animal species and willalter to adapt to pulmonary structure and the physiological demands put on thelungs Values for the PC16:0/16:0 content in native mammalian surfactantsvary between 35.6% for rabbit and 54% for humans (15) and in therapeutic sur-factants from 39.4% in bovine Alveofact to 50.2% in porcine Curosurf (16).Examples of ESI-MS analysis of lung surfactant PtdCho are shown in Fig 1.2,which details mass spectra of material isolated from adult mouse, rabbit, andhuman lungs Apart from the variation in PC16:0/16:0, it is clear that surfactantPtdCho from all these animals contains the same overall range of molecular

700

m/z 0

720.9

761.0 735.9

759.0 757.0 762.0

786.9 763.0 784.9

736.6

760.7

806.6 786.7 782.7 761.7

787.7 807.6 834.8

734.8

732.8 706.8

735.8

760.9 758.9 761.9

786.9 782.9 788.9

PC16:0/1PC16:0/1

species, but with different distributions Strikingly, all surfactants analyzedcontained predominantly 16:0 at their sn-1 position, with sn-1 stearoyl andsn-1 oleoyl together accounting for ,10% These surfactants contained essen-tially only four major PtdCho molecular species other than PC16:0/16:0 andsmall amounts of polyunsaturated species As will be discussed later, PC16:0/18:2 and PC16:0/18:1 are major components of plasma lipoprotein and inflam-matory cell membrane PtdCho, respectively, in addition to being minor com-ponents of surfactant In contrast, PC16:0/14:0 and PC16:0/16:1 are minorcomponents of cell membrane PtdCho and can be regarded as diagnostic for sur-factant This conclusion is supported by metabolic labeling experiments showingidentical kinetics for the incorporation of [3H]choline into alveolar PC16:0/14:0,PC16:0/16:1, and PC16:0/16:0 for mouse and perfused rat lungs (17) The com-bined synthesis and synthetic rates of these three species were all greater thanthose of longer chain monounsaturated species such as PC16:0/18:1.

In most mammalian surfactants, with the exception of the rhesus monkey(18) and newborn piglet (unpublished data) where PtdIns predominate, theanionic phospholipids PtdGly, generally, is the most abundant surfactant glycero-phospholipid after PtdCho When compared with PtdCho, PtdGly has a muchgreater variation between different animal species Schlame et al (19) foundrat surfactant PtdGly to contain 26.7% PG16:0/18:1, 16.9% PG16:0/16:0,11.2% PG16:0/20:4, and 10.6% PG16:0/22:6 Using similar HPLC techniques,Akino and coworkers (2) reported rabbit surfactant PtdGly to contain 34.7%PG16:0/16:0, 32% PG16:0/18:1, and 10.5% PG16:0/18:2 with negligible poly-unsaturated species In contrast, human lung surfactant PtdGly has a verydifferent composition to either rat or rabbit, being dominated by three mono-unsaturated species with low amounts of PG16:0/16:0 (15) This variation ofPtdGly composition between animal species is shown clearly by the spectradetailed in Fig 1.3

The variation in PtdIns composition between different animal species iseven more striking (Fig 1.4) PI16:0/16:0 was a minor component of surfactantPtdIns from all animals, whereas human and rabbit surfactant PtdIns were essen-tially monounsaturated (15) However, although human surfactant PtdIns com-prised largely three species in approximately equal proportions (PI16:0/18:1,PI18:1/18:1, PI18:0/18:1), rabbit surfactant PtdIn was dominated by PI16:0/18:1 as a single species In complete contrast, the dominant species of ratPtdIns was PI18:0/20:4, and this difference was even more marked in themouse Although the anionic phospholipids PtdGly and PtdIns apparently canreplace each other in their contribution to the dynamic properties of alveolar sur-factants (18), their relation to respiratory physiology is even less clear than forPtdCho composition, which correlates with respiratory rate (20) In addition, it

is not clear how differences in surfactant phospholipids composition related tothe significant differences in both the macroscopic and microscopic structures

of lungs from varied mammalian species (21)

742.6 740.6

793.5 748.6

768.6 766.7 749.6 762.6

769.6 770.6

792.6 775.5

794.5 795.5

747.8

721.7 718.8 712.6

700.7704.7

714.7 722.7 745.8

744.8 732.8 723.7

740.7 733.8

748.8

768.8 749.8

766.8 758.9 756.8

794.7 769.8773.7 792.7 778.7 790.8 795.7 804.8802.8 806.8

775.7 748.8

749.8

768.8 750.8 761.7 766.8

776.7 778.7

795.7 794.7 788.7 797.8

857.5 841.6 847.6 848.7 861.6 865.6867.6

886.5

887.6

909.5 888.6 911.6

915.4

835.8

833.8 820.8 804.8806.8 818.8

809.7 821.8 831.8

836.8

861.8 837.7

859.8 848.9 844.8

863.7

885.8 874.9 870.8 875.8 886.8890.8 903.0 910.7914.7

863.7

861.7 835.8

804.8

821.8 820.8 806.8

816.8 822.8824.8833.8

836.8

844.8 837.8 859.7 850.8

864.7

885.8 865.9 884.8876.8 866.9

886.8 890.8 904.8 903.0 912.8913.7

PI18:0/2 PI16:0/2

PI16:0/1

PI18:0/1 PI18:1/1

III Molecular Species of Surfactant Phospholipid DuringFetal Development

The development of the surfactant system during late fetal growth is extremelywell documented For many years, the ratio of PtdCho to sphingomyelin(lecithin:sphingomylein or L:S) or the appearance of PtdGly in amniotic fluidhas been used as indicators of fetal lung maturity (22 – 24) However, at leastfor PtdCho, this development is also accompanied by significant alterations tothe molecular species of surfactant No information is available for the molecularspecificity of surfactant PtdGly or PtdIns during fetal development

PtdCho from immature human fetal lung and liver at 15 weeks of gestation,before the expression of the surfactant system, is largely monounsaturated com-prising almost 50% PC16:0/18:1 (25) It is significant, however, that the sameanalysis showed immature fetal lung PtdCho to contain 25% PC16:0/16:0 Sub-sequent tissue differentiation until term was then characterized by increasingunsaturation of liver PtdCho and increasing saturation of lung PtdCho, both atthe expense of temporal decreases in PC16:0/18:1 content (25,26) However,the greatest fractional increases in PtdCho molecular species during fetal lungdevelopment are not only restricted to PC16:0/16:0, but also involve inPC16:0/16:1 and, particularly, PC16:0/14:0 Importantly, turnover rates ofboth PC16:0/16:0 and PC16:0/14:0 are 3-fold decreased at end gestation,leading to an accumulation of these components not only in guinea pigs (27)but also in human fetuses (20)

IV Molecular Species of Phospholipid During

Postnatal Development

In surfactants, PtdCho molecular species comprise 80% of total phospholipids.Both across mammalian and even avian species, and independent from postnatalage, the sum of PC16:0/16:0, PC16:0/14:0, and PC16:0/16:1 comprise

75 – 80% of total PtdCho (12,28) In general, there is a negative correlationbetween the fraction of PC16:0/16:0 and respiratory rate, whereas PC16:0/14:0 and/or PC16:0/16:1 positively correlate with respiratory rate Conse-quently, PC16:0/16:0 concentration is lower in neonatal when compared withadult mammals, whereas PC16:0/14:0 and/or PC16:0/16:1 are increased Strik-ingly, during alveolarization of rat and mouse lungs between days 4 and 14 afterbirth when respiratory rate increased to 300 – 400 min21, the concentration ofPC16:0/16:0 was low at 33% of total PtdCho In contrast, at the same postnatalage, PC16:0/14:0 comprised some 25 – 27% of total PtdCho when compared with,10% in adult animals (20)

The physiological meaning of such compositional changes, however, is stillunclear High respiratory rates may cause a positive end-expiratory pressurethat stimulates branching and organ development, precludes collapse of the