Oxidative Stress in Lung Diseases: Volume 2 [1st ed. 2020] 978-981-32-9365-6, 978-981-32-9366-3

Table of contents :
Front Matter ....Pages i-xvi
Front Matter ....Pages 1-1
The Effects of Free Radicals on Pulmonary Surfactant Lipids and Proteins (Mustafa Al-Saiedy, Francis Green, Matthias Amrein)....Pages 3-24
Oxidative Stress in Experimental Models of Acute Lung Injury (Daniela Mokra, Juraj Mokry)....Pages 25-57
Potential of Mesenchymal Stem Cells in Modulating Oxidative Stress in Management of Lung Diseases (Rituparna Chaudhuri, Manisha Singh, Sujata Mohanty)....Pages 59-73
Role of NADPH Oxidase-Induced Oxidative Stress in Matrix Metalloprotease-Mediated Lung Diseases (Jaganmay Sarkar, Tapati Chakraborti, Sajal Chakraborti)....Pages 75-101
Oxidative Stress Mechanisms in the Pathogenesis of Environmental Lung Diseases (Rajesh K. Thimmulappa, Indranil Chattopadhyay, Subbiah Rajasekaran)....Pages 103-137
Front Matter ....Pages 139-139
Oxidative Stress-Induced Mitochondrial Dysfunction and Asthma (Samarpana Chakraborty, Kritika Khanna, Anurag Agrawal)....Pages 141-160
Regulation of Antioxidant Nrf2 Signaling: An Important Pathway in COPD (Nirmalya Chatterjee, Debamita Chatterjee)....Pages 161-175
Role of Oxidative Stress Induced by Cigarette Smoke in the Pathogenicity of Chronic Obstructive Pulmonary Disease (Anuradha Ratna, Shyamali Mukherjee, Salil K. Das)....Pages 177-211
Oxidative Stress in Obstructive and Restrictive Lung Diseases (Elena Bargagli, Alfonso Carleo)....Pages 213-222
TRP Channels, Oxidative Stress and Chronic Obstructive Pulmonary Disease (Amritlal Mandal, Anup Srivastava, Tapati Chakraborti, Sajal Chakraborti)....Pages 223-243
Paraquat-Induced Oxidative Stress and Lung Inflammation (Namitosh Tyagi, Rashmi Singh)....Pages 245-270
Environmental and Occupational agents and Cancer Drug-Induced Oxidative Stress in Pulmonary Fibrosis (Tapati Chakraborti, Jaganmay Sarkar, Pijush Kanti Pramanik, Sajal Chakraborti)....Pages 271-293
Front Matter ....Pages 295-295
Respiratory Syncytial Virus-Induced Oxidative Stress in Lung Pathogenesis (Yashoda Madaiah Hosakote, Kempaiah Rayavara)....Pages 297-330
Reactive Oxygen Species: Friends or Foes of Lung Cancer? (Deblina Guha, Shruti Banerjee, Shravanti Mukherjee, Apratim Dutta, Tanya Das)....Pages 331-352
Role of Noncoding RNA in Lung Cancer (Angshuman Bagchi)....Pages 353-362
Reactive Oxygen Species (ROS): Modulator of Response to Cancer Therapy in Non-Small-Cell Lung Carcinoma (NSCLC) (Shamee Bhattacharjee)....Pages 363-383
Lung Cancer: Old Story, New Modalities! (Urmi Chatterji)....Pages 385-409
Front Matter ....Pages 411-411
The Use of Ozone as Redox Modulator in the Treatment of the Chronic Obstructive Pulmonary Disease (COPD) (Emma Borrelli)....Pages 413-426
Oxidative Stress and Therapeutic Development in Lung Cancer (Animesh Chowdhury, Sarita Sarkar, Soma Ghosh, Ashish Noronha, Tapati Chakraborti, Sajal Chakraborti)....Pages 427-443
Regulation of Oxidative Stress by Nitric Oxide Defines Lung Development and Diseases (Suvendu Giri, Sumukh Thakar, Syamantak Majumder, Suvro Chatterjee)....Pages 445-464
Epidermal Growth Factor Receptor: Promising Targets for Non-Small-Cell Lung Cancer (Della Grace Thomas Parambi, K. M. Noorulla, Md. Sahab Uddin, Bijo Mathew)....Pages 465-471
Oxygenated Lipid Products in COPD and Asthma: A Clinical Picture (Debamita Chatterjee)....Pages 473-488

Citation preview

Sajal Chakraborti Narasimham L. Parinandi · Rita Ghosh Nirmal K. Ganguly · Tapati Chakraborti Editors

Oxidative Stress in Lung Diseases Volume 2

Oxidative Stress in Lung Diseases

Sajal Chakraborti Narasimham L. Parinandi Rita Ghosh  •  Nirmal K. Ganguly Tapati Chakraborti Editors

Oxidative Stress in Lung Diseases Volume 2

Editors Sajal Chakraborti Department of Biochemistry and Biophysics University of Kalyani Kalyani, West Bengal, India Rita Ghosh Department of Biochemistry and Biophysics University of Kalyani Kalyani, West Bengal, India Tapati Chakraborti Department of Biochemistry and Biophysics University of Kalyani Kalyani, West Bengal, India

Narasimham L. Parinandi Department of Internal Medicine The Ohio State University Columbus, OH, USA Nirmal K. Ganguly Apollo Hospitals Educational & Research Foundation (AHERF) Indraprastha Apollo Hospitals New Delhi, Delhi, India

ISBN 978-981-32-9365-6    ISBN 978-981-32-9366-3 (eBook) https://doi.org/10.1007/978-981-32-9366-3 © Springer Nature Singapore Pte Ltd. 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

This book is dedicated to Prof. Amartya Sen (Nobel Prize winner in Economic Sciences in the year 1998) for his outstanding contribution in human welfare economics devoted to ameliorate inequality and poverty. Prof. Sen was born in Santiniketan on 3rd November 1933 on the campus of Rabindranath Tagore’s Visva-Bharati University. He spent some of his childhood in Dhaka (now in Bangladesh) and was educated there at the St. Gregory School. His father, Prof. Asutosh Sen, taught chemistry at the Dhaka University. However, it was at Santiniketan where his educational attitudes were formed. After schooling at Santiniketan, Prof. Sen studied at Presidency University in Calcutta, where his intellectual horizon was

radically broaden. After graduation, he moved to Trinity College in Cambridge. He later taught at both these universities, and also at Delhi University, London School of Economics, Oxford University, and Harvard University, and on a visiting basis at MIT, Stanford, Cornell, and the University of California at Berkeley. Prof. Sen has devoted his career mostly on the well-being of the community. In several writings, he addressed problems such as individual rights, majority rule, and the availability of information about individual lives, which inspired many researchers to turn their attention to basic welfare of common people. His views eventually prompted policy-makers of different developing countries to find ways to enhance well-being of the poor through public works project. He is a vigorous defender of academic freedom, possible education, and public health system. Prof. Sen undoubtedly is a legendary international figure, who devoted most part of his academic and social life for the development of the poor. He has excellent ability to motivate young researchers. His novel insight to explore and amalgamate philosophy with economics for human welfare is amazing. He is truly a genius. We feel honoured to dedicate this book to Prof. Amartya Sen and wish him good health in his long fruitful activities. Kalyani, West Bengal  India

Sajal Chakraborti

Preface

“Queen: O Hamlet, thou hast cleft my heart in twain. Hamlet: Oh, throw away the worser half, and live a purer life with the other!” (William Shakespeare: Hamlet: Act 3; scene-4)

The numbers of diseases in which detrimental oxidation processes play aggravating roles have grown steadily over the past two decades. Among the diseases, oxidantinduced lung diseases are the most prevalent in humans. “Oxidative stress” indicates a disturbance in the pro-oxidant/antioxidant balance and swings it in favour of the pro-oxidants, leading to potential damage to various components of cells and tissues. The novel roles of oxidants and antioxidants as mediators in signalling cascades have opened new areas of active research. This book provides chapters with evidence for crucial roles of oxidants and antioxidants in regulating different types of lung diseases. This book focuses on some new strategies of antioxidant defence counting new pharmacologically active agents, presents current knowledge of known agents, and provides possible therapeutics of different lung diseases. It is hoped that the book will serve as a potential stimulus for further research. Considering the progression of a plethora of research in this area, it is possible that some of the propositions made by the contributors may eventually turn out to be otherwise. A Harvard biochemist once said to his graduate students that “half of what we taught is probably wrong, but at this stage, we do not know which half”. Gottfried Schatz (former Secretary General of EMBO, former President of Swiss Science and Technology Council, and former Editor of The FEBS Letters) once said that “the uncertainty of scientific knowledge is not weakness, but strength. The scientific vision of the world has dynamic stability. It is not chained to facts, but in a way of looking at them. Most institutions demand absolute faith, but science makes scepticism a virtue. Scientists see the world as it is and not as they want it to be”. This book is an outcome of enthusiasm of various renowned experts in their relevant research areas and contains four subdivisions. Part 1 describes the general aspects of reactive oxygen species-mediated lung diseases; Part II enumerates chronic lung diseases like asthma, COPD, inflammatory lung diseases, and lung fibrosis; Part III provides notable information on respiratory syncytial virus (RSV)induced lung diseases and different aspects of lung cancer; and Part IV deals with vii

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prevention and therapeutics. Each chapter in this book raises many questions that need to be addressed for finding appropriate solutions in the area of oxidant-induced lung diseases. We are greatly indebted to all contributors for their considerable energy, time, and effort to accomplish a complete chapter with no quid pro quo benefit. We would like to thank Mr. Lenold Esithor and Dr. Madhurima Kahali (Springer Nature) for their cooperation and support during the preparation of the book. Kalyani, West Bengal, India

Sajal Chakraborti

About the Book

This book is intended to provide multidisciplinary approach demonstrating cellular and molecular mechanisms associated with ROS-induced initiation and progression of a variety of lung diseases such as COPD, emphysema, asthma, cystic fibrosis, occupational pulmonary diseases, and importantly lung cancer. The book also covers translational research on lung diseases and recent research on the prevention and therapeutics of different types of lung diseases. Considering the depth and plethora of information to be covered, each article of this book are immensely useful for the researchers working on understanding the mechanisms associated with different types of lung diseases and to identify targets for drug development. With this multidisciplinary scope, this book will bridge the gap between fundamental and translational research with its application in biomedical and pharmaceutical industry, making it a thought-provoking reading for basic and applied scientists engaged in biomedical research.

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Contents

Part I General Aspects of Reactive Oxygen Species-Mediated Lung Diseases 1 The Effects of Free Radicals on Pulmonary Surfactant Lipids and Proteins����������������������������������������������������������������������������������������������    3 Mustafa Al-Saiedy, Francis Green, and Matthias Amrein 2 Oxidative Stress in Experimental Models of Acute Lung Injury��������   25 Daniela Mokra and Juraj Mokry 3 Potential of Mesenchymal Stem Cells in Modulating Oxidative Stress in Management of Lung Diseases������������������������������������������������   59 Rituparna Chaudhuri, Manisha Singh, and Sujata Mohanty 4 Role of NADPH Oxidase-Induced Oxidative Stress in Matrix Metalloprotease-Mediated Lung Diseases ��������������������������������������������   75 Jaganmay Sarkar, Tapati Chakraborti, and Sajal Chakraborti 5 Oxidative Stress Mechanisms in the Pathogenesis of Environmental Lung Diseases������������������������������������������������������������  103 Rajesh K. Thimmulappa, Indranil Chattopadhyay, and Subbiah Rajasekaran Part II Chronic Lung Diseases 6 Oxidative Stress-Induced Mitochondrial Dysfunction and Asthma ����������������������������������������������������������������������������������������������  141 Samarpana Chakraborty, Kritika Khanna, and Anurag Agrawal 7 Regulation of Antioxidant Nrf2 Signaling: An Important Pathway in COPD������������������������������������������������������������������������������������  161 Nirmalya Chatterjee and Debamita Chatterjee 8 Role of Oxidative Stress Induced by Cigarette Smoke in the Pathogenicity of Chronic Obstructive Pulmonary Disease ������  177 Anuradha Ratna, Shyamali Mukherjee, and Salil K. Das

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9 Oxidative Stress in Obstructive and Restrictive Lung Diseases����������  213 Elena Bargagli and Alfonso Carleo 10 TRP Channels, Oxidative Stress and Chronic Obstructive Pulmonary Disease����������������������������������������������������������������������������������  223 Amritlal Mandal, Anup Srivastava, Tapati Chakraborti, and Sajal Chakraborti 11 Paraquat-Induced Oxidative Stress and Lung Inflammation ������������  245 Namitosh Tyagi and Rashmi Singh 12 Environmental and Occupational agents and Cancer Drug-Induced Oxidative Stress in Pulmonary Fibrosis ����������������������  271 Tapati Chakraborti, Jaganmay Sarkar, Pijush Kanti Pramanik, and Sajal Chakraborti Part III Other Lung Diseases 13 Respiratory Syncytial Virus-Induced Oxidative Stress in Lung Pathogenesis ������������������������������������������������������������������������������  297 Yashoda Madaiah Hosakote and Kempaiah Rayavara 14 Reactive Oxygen Species: Friends or Foes of Lung Cancer?��������������  331 Deblina Guha, Shruti Banerjee, Shravanti Mukherjee, Apratim Dutta, and Tanya Das 15 Role of Noncoding RNA in Lung Cancer����������������������������������������������  353 Angshuman Bagchi 16 Reactive Oxygen Species (ROS): Modulator of Response to Cancer Therapy in Non-Small-Cell Lung Carcinoma (NSCLC) ������������������������������������������������������������������������������  363 Shamee Bhattacharjee 17 Lung Cancer: Old Story, New Modalities!��������������������������������������������  385 Urmi Chatterji Part IV Prevention and Therapeutics 18 The Use of Ozone as Redox Modulator in the Treatment of the Chronic Obstructive Pulmonary Disease (COPD) ��������������������  413 Emma Borrelli 19 Oxidative Stress and Therapeutic Development in Lung Cancer ������  427 Animesh Chowdhury, Sarita Sarkar, Soma Ghosh, Ashish Noronha, Tapati Chakraborti, and Sajal Chakraborti

Contents

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20 Regulation of Oxidative Stress by Nitric Oxide Defines Lung Development and Diseases������������������������������������������������������������  445 Suvendu Giri, Sumukh Thakar, Syamantak Majumder, and Suvro Chatterjee 21 Epidermal Growth Factor Receptor: Promising Targets for Non-Small-­Cell Lung Cancer�����������������������������������������������������������  465 Della Grace Thomas Parambi, K. M. Noorulla, Md. Sahab Uddin, and Bijo Mathew 22 Oxygenated Lipid Products in COPD and Asthma: A Clinical Picture ������������������������������������������������������������������������������������  473 Debamita Chatterjee

About the Editors

Dr. Sajal Chakraborti is a Professor of Biochemistry at the University of Kalyani, West Bengal, India. His research focus is on the role of proteases, oxidant, and Ca2+ signaling phenomena in the pathogenesis of lung diseases. He received Ph.D. from the Calcutta University in the year 1982 and his D.Sc. from the Kalyani University in the year 2004. He did postdoctoral research at the Johns Hopkins University, University of Utah, and New York Medical College as a Fulbright Fellow in 1987– 1990. He received DBT-Senior Overseas Research Award for his research at the Brain Institute, University of Florida, Gainesville, Florida, in 1999. He has been involved in teaching and research in Biochemistry for the past 40  years. He has published over 110 original research papers, 22 book chapters, and 15 review articles and also edited 12 books published by Springer.  

Dr. Narasimham L. Parinandi is an Associate Professor in the Pulmonary Division of the Department of Medicine at the Ohio State University, Columbus, Ohio. He earned his Ph.D. in the year 1986 from the University of Toledo, Toledo, OH, USA. Dr. Parinandi did postdoctoral research at the Hormel Institute, University of Minnesota, and also at the Johns Hopkins University School of Medicine. Dr. Parinandi has published over 100 research papers and edited a book on free radicals and antioxidant protocols.  

Dr. Rita Ghosh is a Professor of Biophysics in the Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India. She obtained Ph.D degree from the Calcutta University and did postdoctoral research at the Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland in 1991–1993. Her research focuses on the different aspects of cell biology and radiation biology. She has been engaged in teaching and research for over 30 years and published over 40 original research papers, and has written some review articles and book chapters.  

Dr.  Nirmal  K.  Ganguly was the Director General, Indian Council of Medical Research (ICMR), New Delhi. He is currently associated with  the Translational Health Science and Technology Institute, Faridabad, India. He has published over 700 research papers and edited several book chapters and review articles.  

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Dr. Tapati Chakraborti is a Professor of Biochemistry at the University of Kalyani, West Bengal, India. She did  Ph.D degree at  the Jadavpur University, Kolkata, in 1992, and did postdoctoral research at the Brain Institute, University of Florida, Gainesville, Florida as a Fellow of the American Heart Association in 1999–2002. She has been actively involved in teaching and research for the past 30 years, and one of the important aspects of her research focuses on the regulation of pulmonary vascular tone under stimulation of vasoactive agents. She has published over  80 original research papers, 18 book chapters, and 12 review articles and also edited 3 books entitled published by Springer.  

Part I General Aspects of Reactive Oxygen Species-­Mediated Lung Diseases

1

The Effects of Free Radicals on Pulmonary Surfactant Lipids and Proteins Mustafa Al-Saiedy, Francis Green, and Matthias Amrein

Abstract

The pulmonary surfactant forms a mixed protein–lipid film at the air–lung interface. It plays a dual role of surface tension reduction and host defense against inhaled pathogens. In acute lung injury (ALI) and its more severe form of acute respiratory distress syndrome (ARDS), high surface tension throughout the lung results in intrapulmonary shunts and edema leading to atelectasis and hypoxemia. Pulmonary surfactant inhibition is associated with various pulmonary diseases. ALI/ARDS is common (150,000 new cases per year in the United States) with mortality ranging from 30% to 60% depending on disease stage. High surface tension can result from an absence of a surfactant film over significant portions of this interface, or from the presence of dysfunctional layer of surfactant. Elevated cholesterol levels are shown to be a potent surfactant inhibitor. Oxidative damage to both phospholipids and proteins is shown to inhibit surfactant function. The pulmonary surfactant may be degraded by reactive oxygen and nitrogen (RONS) species in the inflamed lung in the presence of physiological cholesterol levels. The inhibitory mechanism of oxidative damage on the surfactant film is outlined in this chapter. Lipid-sequestering therapies, including cyclodextrins, may offer a potential treatment to restore surfactant function and reduce pulmonary inflammation. Keywords

Pulmonary surfactant dysfunction · Oxidation · Cholesterol · Surfactant protein · Phospholipids · Peroxidation · Epoxidation · Peroxynitrites · Cyclodextrins

M. Al-Saiedy · F. Green · M. Amrein (*) Cumming School of Medicine, Department of Cardiovascular & Respiratory Sciences, University of Calgary, Calgary, AB, Canada © Springer Nature Singapore Pte Ltd. 2020 S. Chakraborti et al. (eds.), Oxidative Stress in Lung Diseases, https://doi.org/10.1007/978-981-32-9366-3_1

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1.1

M. Al-Saiedy et al.

Introduction

The pulmonary surfactant is a protein and lipid mixture, secreted by the epithelium into the alveolar lining fluid, which spreads into a surface-active film at the air–lung interface. The film reduces surface tension of the air–water interface (about 70 mN/m) to 10% of total surfactant phospholipids [8, 9]. Neutral lipids, primarily cholesterol, are 2–10% of pulmonary surfactant by weight. PS also contains four surfactant-associated proteins – SP-A, SP-B, SP-C, and SP-D [8]. There are two forms of surfactant aggregates, a highly surface-active form, referred to as the large aggregates, which is enriched in the hydrophilic protein SP-A and hydrophobic proteins SP-B and SP-C, and inactivated form referred to as the small aggregates. SP-A and SP-D’s main functions are innate host defense, whereas SP-C and SP-B are required for the surface-tension lowering property of surfactant [1, 10, 11]. The complex mixture of the surfactant film, which includes a high proportion of DPPC, is thought necessary for the surfactant system to achieve low minimum surface tension during the film compression occurring at expiration. Additionally, it appears that the surfactant film requires unsaturated phospholipids to act as liquefiers for efficient surface adsorption and reinsertion of material during film expansion during inspiration [12].

1  The Effects of Free Radicals on Pulmonary Surfactant Lipids and Proteins

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Surfactant function has been studied in situ, in the lung, and fluctuates during the breathing cycle between about 10 mN/m and 0 [13, 14]. The early work on surfactant function and stability showed the surfactant film in a functional state in lipid monolayer and multilayer regions at the air–lung interface. This structure can be reproduced in vitro to study the structure–function relationship in details [1, 15]. To assess surfactant function in vitro, captive bubble surfactometer (CBS) may be used. CBS comes close to mimicking lung function as determined in vivo from pressure–volume studies [16, 17]. The CBS resembles near-physiological conditions and includes temperature (37 °C), dynamic cycling rates (20 cycles/min), and interfacial adsorption from minute volumes of concentrated (27 mg/mL) surfactant containing dense aggregates [18]. Surfactant film functional assessment begins with measurements of film formation, indicated by the fall of surface tension upon surfactant spreading. Subsequently, the measurement of surface tension upon dynamic compression–expansion cycling is performed. The minimal surface tension (MST) reached during film compression is the primary indicator of surfactant function in this test. The amount of area reduction required to reach MST is another indicator of function. Surfactants tested to date include a clinically used, animal-derived surfactant, such as bovine lipid extract surfactant (BLES) that contains both hydrophobic surfactant proteins and the lipids, surfactants extracted from bronchoalveolar lavage (BAL) of animal models of health and disease, as well as patient surfactants. To study the structure–function relationship, surfactants may be spread to the air–water interphase of a Langmuir trough, surface tension lowered by adjusting the film area, the film lifted off the surface by the Langmuir–Blodgett technique and imaged in an atomic force microscope. These studies show that the lipids of the surfactant accumulate in the interface with the hydrophilic head groups exposed to the water and the hydrophilic tail groups stretched out toward the air in a tightly packed film. Functional surfactant, in addition to this monomolecular lipid film, shows multilayered regions scattered over the surface. The multilayer regions of the film are 5  nm or multiples thereof high, consistent with lipid bilayer stacks. By comparing the structure of functional (Fig.  1.1c–e) and dysfunctional surfactants ([1, 16, 19], Fig. 1.2) as well as theoretical considerations ([15], Fig. 1.1f), stacks act as reinforcing elements that prevent the film from buckling at low surface tension. Buckling is the out-of-plane deflection of the film that leads to film collapse [1]. The surfactant proteins SP-B and SP-C cross-link the bilayers to the monolayer. This attachment is essential (Fig. 1.1b). Otherwise, they would glide over the monolayer and have a little mechanical effect (Fig. 1.1c demonstrates cross-linking). Surfactant-associated proteins B and C (SP-B and SP-C) independently enhance film stability and spreading by facilitating the recruitment of saturated and unsaturated phospholipids into the expanding film (Fig. 1.1e [20]). The positive charges of SP-B and SP-C proteins are essential for their activity. The positive charge allows for interactions with PG and other anionic surfactant phospholipids, critical to film adsorption. Additionally, SP-B and SP-C are essential for the formation of tubular myelin, the tubular meshwork the surfactant unfolds into upon release from the type II cells. Tubular myelin then promotes the rapid phospholipid insertion into the

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Fig. 1.1 (a) Captive bubble surfactometer. The surfactant is spread at the air–buffer interface of a trapped bubble and its size varied while measuring surface tension (surface tension is calculated from the shape of the bubble). This procedure reproduces surfactant performance in the lung during the breathing cycle [19]. (b) Surface tension during cycles (color coded). Functional surfactant drops to a near-zero value upon area reduction, where a dysfunctional surfactant stays at about 20  mN/m (i.e., the equilibrium surface tension of most lipids). (c) AFM micrograph in three-­ dimensional representation of surfactant (5 μm × 5 μm). The film shows stacks of bilayers. Each layer is five nanometers high. (d) AFM topography of the bovine-derived BLES (left) and electrical surface potential of the region (right). SP-C is a strong molecular dipole that gives rise to the high surface potential in the lamellae [22]. (e) Lamellae of surfactant are cross-linked to the monolayer, whereas lamellae of pure lipid films are not. Films of pure lipids (DPPC, top row) and pulmonary surfactant (BLES, bottom row) were imaged by AFM (left column). At this point, partially collapsed lipid films appear no different from surfactant films. However, lamellae of pure lipids can be scraped off from the monolayer in an AFM without trace (top right). Lamellae of surfactant cannot be easily scraped off and leave a trace, indicating that monolayer and lamellae are cross-­ linked (bottom right). (f) Surfactant film may fail by buckling (i.e., moving out of plane). Computational finite element analysis of the critical buckling load as a function of the coverage of the interface by lamellae (the role of multilayer structures in preventing premature surfactant film buckling) explains the stabilizing effect of the lamellae. For a film to resist surface tension without collapse, about 20% of the area or more needs to be covered by lamellae. The lamellae need to be cross-linked to the film. (g) sketch of the cross-linking function of SP-C. Surface tension (arrows) excerpts lateral pressure on the film. The film withstands the pressure. The multilayers locally distribute the load (symbolized by springs) and prevent buckling

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air–liquid interface, regulating the molecular ordering of the film, and the formation of multilayer structures (Fig. 1.1g) [21].

1.3

 iseases That Are Associated with Surfactant D Dysfunction

Pulmonary surfactant function is impaired in acute respiratory distress syndrome (ARDS), impacting lung health and survival. With up to 34 cases per 100,000 population per year [16], ARDS is common and constitutes a high burden for the healthcare system and society with a cost of well over $100,000 per patient in Canada for acute care, for example. In ARDS, a defect in pulmonary surfactant leads to high surface tension, causing alveolar collapse, intrapulmonary shunts, and edema leading to hypoxemia, a dominant factor in the morbidity and high mortality. Direct respiratory failure accounts for about 15% of deaths [23]. In addition, mechanical stress between overinflated and collapsed lung regions strongly amplifies local and systemic inflammation and may help explain the high incidence of multi-organ dysfunction (MODS). ARDS with MODS has much higher mortality, up to 80% [23]. Surfactant dysfunction as a major pathogenic factor for ARDS has not been treatable to date [23–27]. Bronchiolitis associated with cystic fibrosis (CF) is characterized by inflammation in the distal airways and impaired surfactant function [28]. In vitro testing of pediatric CF surfactant samples, obtained largely from medium and small airways, revealed that the ability of the pulmonary surfactant to maintain patency of a capillary tube was markedly reduced, a finding that may explain obstructed airflow in CF [28, 29]. Surfactant dysfunction correlates with the severity of pulmonary impairment as reflected by FEV1. Other conditions associated with surfactant impairment include pneumonia [30, 31], non-CF bronchiolitis [28], ventilator-induced lung injury (VILI) [32], common complication of mechanical ventilation [7], asthma [33], chronic obstructive pulmonary disease (COPD [33]), neonatal respiratory distress syndrome due to meconium aspiration [34], and Niemann–Pick disease [35].

1.4

Mechanisms of Surfactant Inhibition

Surfactant inhibition refers to the processes that reduce or abolish surfactant surface activity. These processes interfere with surfactant unfolding and adsorption, and film formation interferes with film compression and its ability to reach low surface tensions, or affect surfactant film respreading during expansion [8]. In neonates, however, Avery has shown that impaired lung function in neonatal respiratory distress syndrome (NRDS) is caused by a lack of pulmonary surfactant [36]. This led to the well-established and successful treatment by intratracheal administration of exogenous surfactant. ARDS, on the other hand, is associated with dysfunction, rather than lack of surfactant. According to the standard model, exudative proteins

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and/or other surface-active substances adsorb to the air–lung interface. High surface tension would then result from an absence of a surfactant film over significant portions of this interface [37]. However, exudative proteins are readily displaced by surfactant at the interface and do not result in lasting inhibition [8, 38], and high surface tension is best attributed to impairment of the film itself [26, 39]. Small amphiphilic molecules such as cholesterol, lysolipids, and free fatty acids in the surfactant film may render it dysfunctional [1, 32, 38]. The detrimental effect of surfactant proteins and lipid oxidation by reactive oxygen species (ROS) produced in the inflamed lung in high levels also falls into this category [2, 18].

1.5

 he Combined Role of Oxidation and Cholesterol T in Surfactant Inhibition

The oxidative milieu of the inflamed lung leads to oxidation that renders the surfactant dysfunctional. Surfactant degradation by reactive oxygen species (ROS) is well established and explained by the influx of inflammatory cells in the injured lung, direct and indirect environmental insults to the lung [2, 40, 41]. Free radicals have been implicated in the pathology of pulmonary disease: asthma, bronchiolitis, cystic fibrosis [28, 44], acute respiratory distress syndrome, chronic obstructive pulmonary disease [42, 43], and acute lung injury [32]. Free radicals are continuously formed in the human body [45]. Oxidative damage results from an imbalance in oxidant–antioxidant equilibrium. There are (i) endogenous and (ii) exogenous sources of radicals in the lung. Endogenous oxidants are mainly formed by enzymatic reactions, such as cyclooxygenase-­dependent and xanthine oxidase peroxidation, or they are produced and secreted by activated inflammatory cells [47], whereas exogenous oxidants (e.g., NO2, O3, and O2) occur naturally from direct exposure to environmental gasses and particles [46]. A balance between oxidants and antioxidants is vital for function, homeostasis of physiological systems. Oxidative damage may originate from the chemical property of oxygen to break up into unstable metabolites (radicals). These radicals can then react with various biomolecules and inactivate their properties [46, 48]. The oxidative dysfunction of surfactant is strictly dependent on the presence of cholesterol, insofar, that its removal reverses surfactant dysfunction for a broad range of diseases [15, 18, 28]. Cholesterol may be removed from surfactant by adding methyl-β-cyclodextrin (MβCD) to the aqueous phase when testing surfactant in vitro or by delivering this substance by inhalation in mice. This restores the normal function of the film [32, 49, 50]. The relatively hydrophobic interior of the toroid-shaped MβCD molecule can host various hydrophobic molecules, including cholesterol. High levels of MβCD can extract notable amounts of cholesterol from interfacial surfactant films [30], cell membranes [29], and unilamellar cholesterol/ phospholipid vesicles [30] into water-soluble cholesterol–cyclodextrin complex. Cholesterol on its own abolishes surfactant function [19] when highly elevated to levels, such as published for some incidences in ARDS [50]. Interestingly, for most pathologies of surfactant, cholesterol is not elevated to a level that is in and of itself

1  The Effects of Free Radicals on Pulmonary Surfactant Lipids and Proteins

9

enough to explain dysfunction, and, yet, removal of cholesterol reverses dysfunction. For these cases, the surfactant oxidation has rendered the surfactant susceptible to mildly elevated or even normal levels of cholesterol. In a recent study with pediatric cystic fibrosis, surfactant samples were unable to sustain normal low surface tensions in the CBS (CF, 13.54 ± 1.37 mN/m versus 2.50 ± 0.88 mN/m for lung-­ healthy controls) (P