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Disease Markers in Exhaled Breath

2002 Edition, October 22, 2002

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ISBN: 978-0-8247-0817-7
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Product Details:

  • Revision: 2002 Edition, October 22, 2002
  • Published Date: October 22, 2002
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 546
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:


This book is designed to summarize exciting recent developments in a rapidly evolving field of lung biology, which could provide basic scientists and clinicians with novel noninvasive methods to monitor disease activity based on molecular analysis of exhaled breath. Undoubtedly, research activities over the past few decades have resulted in the identification of a number of important biochemical pathways, affording us with a better understanding of the biology of lung diseases. Many of these processes result in bioproducts that are released from tissue to the gas phase and can be detected in the exhaled air. Alternatively, the underlying disease may involve reactions that ultimately produce a naturally occurring component in exhaled breath. There is increasing evidence that nitric oxide (NO), carbon monoxide (CO), oxidative end products, and prostanoids are fascinating examples of novel molecular markers in exhaled air that could be used as rapid and noninvasive diagnostic tools in a variety of lung pathologies and in fact some distant organ dysfunction.

Not very surprisingly, a significant number of chapters in this book focus on characteristics of NO in exhaled air. As discussed by Claude Lenfant and Warren Zapol in the introduction to a recent volume in this series, the masterful identification of NO as a principal endogenous mediator precipitated an urge for clinical applications. On the basis of exciting animal experiments, a number of NO-related therapies have been implemented in clinical practice, such as inhibition of NO in septic shock and inhaled NO gas for the treatment of hypoxemic patients. At the same time, many investigators became engaged in studying the characteristics of the endogenous L-arginine-NO pathway in the normal and diseased lung, in both animal models and humans. This activity led to the remarkable discovery of NO in exhaled air by Gustafsson and colleagues in 1991, which launched a decade of considerable progress in understanding how this ‘‘window'' can be used to reflect production and fluid-phase reactions of NO in lung tissue. We have learned much regarding pitfalls of NO determination and produced recommendations for standardization of NO analysis in exhaled air. Finally, we have completed an initial phase of clinical investigations where one can correlate levels of exhaled NO with certain disease activity and response to medical treatment.

Although much of the recent research activity has focused on NO, the diagnostic potential of exhaled breath is by no means limited to NO. There is increasing evidence of another interesting endogenous pathway involving heme oxygenase. The activity of this enzyme leads to the generation of CO, a molecule that exhibits a biological profile similar to that of NO. Recent elegant studies suggest an inducible nature for this pathway, which could be important in limiting stress-induced responses in the lungs. Monitoring CO accumulation in exhaled air appears to be promising, and current investigations suggest that it might provide important information during the course of acute lung injury.

Despite the fact that limited and well-controlled oxidative reactions are being increasingly recognized as participants in cellular signal transduction events, there is no doubt that uncontrolled oxidant stress is the underlying mechanism of a wide variety of lung pathologies, including lung injury associated with ischemia-reperfusion and inflammation. It is therefore crucial that researchers and clinicians have appropriate means to detect the presence of untoward oxidant stress, to monitor the extent of injury and response to therapeutic modalities. Intriguing investigations reveal that oxidant stress-induced changes in cellular membranes lead to accumulation of volatile organic compounds that can be detected in exhaled air. Furthermore, hydrogen peroxide, one of the classical mediators of oxidant reactions, and some oxidative products of arachidonic acid metabolism can be collected in condensates of exhaled air to monitor and to quantify the extent of oxidant stress in the lungs.

This volume brings together current knowledge of the characteristics of novel biological mediators in exhaled breath. This expertise holds the potential for many important aspects of lung disease to be diagnosed and monitored rapidly, noninvasively, and at the bedside. For these reasons, it is not surprising that these methods are being increasingly used in many centers all around the world. However, there are many pitfalls in these measurements, leading to nonuniformity in the reported data. The only way to avoid artifacts is to understand the basic mechanisms involved in the generation and release from lung tissue to the airways of these markers, and their diffusion and distribution characteristics along the airways. Finally, there are important technical aspects of the measurements.

These considerations are reflected in the first two main sections of the book. Part One reviews basic physiological aspects of disease mediators in exhaled breath. We begin by reviewing the general importance of the L-arginine-NO pathway as a primary biological mediator system. Belvisi and coauthors provide important information regarding the mechanisms utilized by different cell types to synthesize NO, the molecular and substrate regulation of the major forms of NO synthases, their inhibitors, and effector mechanisms influenced by NO. The next chapter, by Adding and Gustafsson, reflects on the original discovery of exhaled NO and offers the reader an up-to-date review of progress made on fundamentals of the physiology of exhaled NO, with emphasis on regulatory factors such as atmospheric oxygen, stretch, and endogenously formed carbon dioxide and catecholamines. This invaluable chapter culminates in a comprehensive hypothesis regarding regulation of NO synthesis and its physiological implications in less ventilated lung regions.

Despite the progress regarding many aspects of the exhaled-NO field, there is still considerable uncertainty as to the precise sources of the NO in expired air. The chapter by Deykin and collaborators reviews the enzymatic formation of NO, summarizes the available data to indicate which of these enzymes contributes NO to the expirate, and then discusses the cellular and anatomical compartments from which the NO so formed contributes to the fraction of expired NO. In contrast, one of the earliest and widely accepted findings regarding concentrations of NO in expired air was the demonstration of flow dependency. This can be extended to other important determinants of gas-phase NO. Among these, ventilation parameters and pulmonary blood flow are major factors in influencing measured NO concentration, which is the topic of the next chapter. Understanding these issues has implications not only for exhaled NO physiology but for standardization of clinical measurements and for data interpretation in various pathological conditions.

We then temporarily depart from NO and dedicate two chapters to overviews of the biochemical and physiological regulation of another gaseous molecule, CO. We begin by focusing on heme oxygenase (HO), a remarkable enzyme and highly conserved molecule that seems to be essential for most forms of life. Interestingly, constitutive and inducible isoforms of HO are involved not only in the breakdown of heme but in modulating many cellular and organ responses to oxidative stress and inflammatory stimuli. These issues are reviewed in Chapter 5, by Lee et al., focusing on the modulation of various forms of lung injury and on the potential mechanisms involved in HO-mediated cytoprotection. CO is one of the exciting by-products of HO action, and this extraordinary molecule is the subject of the next chapter, by Otterbein and coworkers. CO has been studied for over 100 years and until the last few years has been touted as a molecule to avoid. Its story resembles that of NO in many ways. After many years of consideration as a toxic gaseous molecule, recent studies demonstrate that CO is an intriguing intra- and intercellular regulator of ever-increasing numbers of physiological responses, which exhibit considerable overlap with NO. Otterbein et al. present here, with much personal enthusiasm, an interesting historical perspective on CO research and summarize compelling reasons for a renewed effort to understand the potentially beneficial effects of this interesting molecule.

One common scenario in a multitude of lung diseases is the episode of a variable degree of oxidative stress. Originally this was described as a series of relatively simple chemical reactions including oxygen-derived free radicals. It appears that the picture has become much more complicated than originally thought, and the intricate interplay between nitrogen-, oxygen-, and carbon-centered free radicals and oxidizing species requires special attention. Since these reactions are at the core of many lung diseases, we include a section discussing these issues in terms of the physiological aspects. Davis and coauthors have provided a state-of-the-art review of the characteristics, the good and dark sides of reactive nitrogen and oxygen species, and their contribution to experimental and clinical lung injury.

Part Two is devoted to methodological aspects and technological issues concerning detection of the proposed disease markers NO, CO, and organic volatile compounds in exhaled air. Kharitonov and Barnes review technical issues and recommendations regarding measurement of NO and CO in the gas phase and techniques to collect breath condensate containing a myriad of potential breath markers. We then discuss methodological aspects of breath analysis involving volatile organic compounds. In Chapter 9, Phillips presents an overview of the advantages and disadvantages of various approaches to collecting, concentrating, and analyzing volatile organic compounds. He also hints at the potential diagnostic value of these markers in several disorders, including cancer, transplant rejection, and heart disease.

Part Three focuses on pathological aspects of disease markers. Instead of reviewing each disease individually, we grouped conditions according to the main pathological features of lung disease, such as hypoxia, ischemia-reperfusion, and inflammation. In the hypoxia section, Dweik and Erzurum review recent data on the acute and chronic effects of hypoxia on lung NO production in animals and humans. Chapter 11, by Kharitonov, deals with characteristics of exhaled NO in primary pulmonary hypertension, a condition in which hypoxia is a dominant feature.

The common scenario in the next two chapters is ischemia-reperfusion. Due to the delicate structure of the alveolar-capillary unit, its huge surface area available for activated leukocyte–endothelial interactions, and the fact that the lung microvasculature receives the entire cardiac output immediately after reperfusion, the lung is especially vulnerable to this type of injury. In light of these considerations, as discussed in the chapter by Ko¨vesi et al., it is quite remarkable that recent studies reveal maintained exhaled NO levels in patients subjected to transient ischemia-reperfusion during cardiac surgery utilizing cardiopulmonary bypass. In contrast, NO completely disappears from the exhaled breath of the majority of lung transplant recipients, suggesting more prominent lung injury with complete lung ischemia. The work by Brown and Risby continues this theme by reviewing mechanisms underlying volatile organic compound production in oxidative stress and by reviewing exciting data regarding monitoring reperfusion injury in a distant organ by analysis of exhaled breath.

A major section of this volume is devoted to issues related to inflammation. Kharitonov and Barnes discuss the biology and biochemical markers of asthma, focusing primarily on NO and CO. This is clearly an area in which monitoring of exhaled NO is already in clinical practice. Stitt and Douglas present evidence from animal studies showing that exhaled NO could be used as an early marker of septic shock. Chapter 16, by Schubert et al., takes this further into clinical practice and demonstrates the complexity of the many simultaneous biological processes underlying the development of adult respiratory distress syndrome and the potential of disease markers to help us to understand these events.

One of the most difficult medical tasks in caring for lung transplant recipients is the differential diagnosis between acute infection and rejection processes. Novel data are provided by Fisher and colleagues regarding characteristics of NO in these conditions.

Cystic fibrosis (CF) occupies a special place in exhaled NO research, because it is one of the few inflammatory disorders that are not accompanied by increased exhaled NO. Kelley and Drumm have done pioneering work in this area, and they summarize characteristics of NO production in CF.

We continue our journey of exhaled markers with an important review of what is currently known about the role of NO in autoimmune and rheumatic disorders. Rolla and Caligaris-Cappio examine the fate of exhaled NO in patients with rheumatic disease with and without lung involvement. Finally, the chapter by Demoncheaux and coauthors investigates the contribution of exhaled NO to total body metabolism of nitrogen oxides and how these events are disturbed in liver diseases.

In order to assemble the best possible account of this rapidly developing field, we have recruited an expert international faculty from leading groups of investigators. The authors represent a wide range of current activities and sound experience with disease markers in exhaled breath. We hope that this monograph will be an asset for investigators and clinicians who wish to widen their diagnostic and monitoring repertoire both in the laboratory and at the bedside. We share the view that—beyond major technological developments of immense commercial applicability, such as ethanol breath testing and capnography—breath analysis has already provided gratifying potential as a noninvasive diagnostic entity for monitoring disease severity and responsiveness to medication at a molecular level. Although we continue to debate many important aspects of this field, we also have the common vision that breath analysis upholds its promise as one of the most exciting and innovative aspects of research in lung biology in health and disease.