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Surface Activity of Pulmonary Surfactant Protein B Surface Activity of Pulmonary Surfactant Protein B From Biophysical Properties to Clinical Application Rob Diemel Surface activity of pulmonary surfactant protein B From biophysical properties to clinical application Robert V. Diemel Ph.D. thesis, with summary in Dutch Utrecht University, the Netherlands January 2002 The studies described in this thesis were performed at the Department of Anaesthesiology and Critical Care Medicine, The Leopold-Franzens-University of Innsbruck, Austria, and at the Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, the Netherlands. Copyright © 2002 by R.V. Diemel. All rights reserved. No part of this thesis may be reproduced or transmitted in any form or by any means, without written permission from the author. Surface Activity of Pulmonary Surfactant Protein B From Biophysical Properties to Clinical Application Oppervlakte-Activiteit van Long Surfactant Eiwit B Van Biofysische Eigenschappen tot Klinische Toepassing (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de Rector Magnificus, Prof. Dr. W.H. Gispen, ingevolge het besluit van het College voor Promoties in het openbaar te verdedigen op 10 januari 2002 des middags te 14.30 uur door Robert Victor Diemel geboren op 29 augustus 1972, te Driebergen-Rijsenburg Promotores: Prof. Dr. L.M.G. van Golde Hoofdafdeling Biochemie & Celbiologie Faculteit der Diergeneeskunde, Universiteit Utrecht Prof. Dr. H.P. Haagsman Hoofdafdeling Voedingsmiddelen van Dierlijke Oorsprong Faculteit der Diergeneeskunde, Universiteit Utrecht Co-promotores: Dr. J.J. Batenburg Hoofdafdeling Biochemie & Celbiologie Faculteit der Diergeneeskunde, Universiteit Utrecht Prof. Dr. G. Putz Universitätsklinik für Anästhesie und allgemeine Intensivmedizin Leopold-Franzens Universität Innsbruck, Österreich The work described in this thesis was financially supported by the Fonds zur Förderung der Wissenschaftlichen Forschung (FWF) (P11527-MED), Austria. The printing of this thesis was financially supported by the Department of Biochemistry and Cell Biology, the Graduate School of Animal Health, Boehringer-Ingelheim (manufacturer of Alveofact®). Printed by Drukkerij Labor, Utrecht, December 2001. CIP-GEGEVENS KONINKLIJKE BIBLIOTHEEK, DEN HAAG Surface activity of pulmonary surfactant protein B. From biophysical properties to clinical application / Robert Victor Diemel.- Utrecht: Utrecht University, Faculteit Diergeneeskunde. Proefschrift Universiteit Utrecht.- With ref.- With summary in Dutch. ISBN 90-393-2958-3 CONTENTS Preface 6 Chapter 1 Surfactant-associated proteins: functions and structural variation 9 Chapter 2 Effect of the hydrophobic surfactant proteins on the surface activity of spread films in the captive bubble surfactometer 27 Chapter 3 Effects of cholesterol on surface activity and surface topography of spread surfactant films 37 Chapter 4 Multilayer formation upon compression of surfactant monolayers depends on protein concentration as well as lipid composition: an atomic force microscopy study 59 Chapter 5 Functional tests for the characterization of surfactant protein B (SP-B) and a fluorescent SP-B analog 79 Chapter 6 In vitro and in vivo-intrapulmonary distribution of fluorescently labeled surfactant 97 Chapter 7 Summarizing discussion 115 Reference list 130 List of abbreviations 148 Samenvatting 149 Dankwoord 156 List of publications 158 Curriculum Vitae 159 Preface Preface The first connection between lungs and surface tension was made in 1929 when it was observed that it takes more pressure to fill up lungs with air than with an aqueous buffer [1]. This demonstrated that the addition of buffer resulted in the elimination of a pulmonary surface tension. From this it was hypothesized that the surface tension in the alveoli can be altered by a surface-active substance, which was later called ‘surfactant’. The properties, function and origin of a surface-active alveolar lining layer were described several decades later [2,3,4]. Shortly thereafter, it was observed that neonatal respiratory distress syndrome, from which prematurely born infants suffer, was related to a deficiency of surface-active material [5]. The important role of dipalmitoyl phosphatidylcholine (DPPC) in surface tension lowering was recognized in the 1960's [6,7]. In the 1970's the presence of proteins in surfactant was shown, leading to a growth in surfactant research [8]. The interest for surfactant leaped in 1980 when surfactant was used successfully in the treatment of prematurely born infants suffering from respiratory distress syndrome [9]. From then on clinicians and scientist made great efforts investigating whether surfactant can be used to treat adult patients suffering from acute respiratory distress syndrome (ARDS) as well [10,11]. Although the results obtained in several clinical studies look promising, a successful therapeutic strategy for ARDS patients has not yet been developed, due to the complex nature of the syndrome as well as to insufficient knowledge on the mode of action of the surfactant components. Therefore, scientific research is performed on individual surfactant components, which will ultimately lead to the development of synthetic surfactants to be used for the treatment of ARDS patients in the clinic. Reduction of the surface tension at the alveolar air/liquid interface is achieved by formation of a surface-active film that consists of a lipid monolayer highly enriched in DPPC, and bilayer or multilayer structures (‘surface-associated reservoir’) closely attached to the monolayer. The presence of a surfactant film prevents the alveoli from collapsing at end- expiration and makes breathing with minimal effort possible. The existence of such a film has been visualized in vivo by electron microscopy [12] and in vitro by atomic force microscopy (AFM) and fluorescence light microscopy [13]. The two hydrophobic surfactant proteins SP-B and SP-C play key roles in the events leading to the formation of a layered surface film as well as in its stabilization. The activities of SP-B include promotion of adsorption of lipids into the air/liquid interface [14], respreading of films from the collapse phase [15], membrane fusion and lysis [16], formation of tubular myelin [17], and surfactant reuptake by type II cells [18]. The importance of SP-B is further documented by the observation that neonates that had a frame-shift mutation in the SP-B gene died from respiratory failure [19]. Similarly, homozygous SP-B knock-out mice died of respiratory failure immediately after birth [20]. Moreover, blocking of SP-B with monoclonal antibodies in rabbits led to respiratory failure and the loss of surfactant activity [21]. Despite the fact that the structures of SP-B and SP-C are quite different, their activities overlap to a large extent. Therefore it was unexpected to 6 Preface find that homozygous SP-C knockout mice are viable [22,23]. In addition to its function to reduce the surface tension, lung surfactant plays an important role in the host defense system of the lung, mediated by the hydrophilic surfactant proteins SP-A and SP-D. The global aim of our studies was to obtain more information about the mechanisms involved in the action of the hydrophobic surfactant components, with a special attention for SP-B. To reach this goal, many different assays and devices were used, including a pressure driven captive bubble surfactometer (CBS), a spreading trough and an atomic force microscope. The thesis starts with a general overview about the function and structural variation of the surfactant proteins (chapter 1). It is described that the activity and structure of the hydrophobic surfactant proteins SP-B and SP-C is very conserved among species throughout evolution, while more variation exists for that of SP-A and SP-D. Aim i) of the thesis research was to obtain knowledge about the effect of SP-B and SP-C on the surface activity of spread films. This study, described in chapter 2, was done using the CBS, an apparatus that allows accurate determination of surface tension under dynamic conditions [24,25,26]. Surfactant components were spread at the air/liquid interface of an air-bubble, which was subsequently repeatedly compressed and expanded, thereby mimicking the breathing cycle. In this way information can be obtained on the role of individual surfactant components. Both SP-B and SP-C activity depended on the concentration of the proteins. Differences in surface dynamics between both proteins were found when lipid vesicles were omitted from the subphase. Aim ii) was to investigate the role of cholesterol in surfactant. The effect of cholesterol on surface tension was examined by CBS, using spread lipid films containing SP-B and/or SP-C (chapter 3). It was shown that a cholesterol content of 10 mol% is optimal for surfactant activity in films containing SP-B, but not in films containing both SP-B and SP-C, or SP-C alone. Furthermore, differences in network structures were seen between films containing and those lacking cholesterol, as visualized by AFM. Aim iii) was to investigate which surfactant components are responsible for the formation of protrusions upon monolayer compression towards low surface tensions (described in chapter 4). The appearance of compressed films containing saturated phospholipids plus native bovine SP-B was visualized by AFM. These films had similar appearance as those containing synthetic peptides based on the 25 N-terminal amino
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