Building on the existing titles in the "Airways Smooth Muscle" sub-series, the sixth volume explores physiological and pharmacological processes in the lung in vivo. The various animal models available for studying the bronchospasm and inflammation associated with human asthma are thoroughly reviewed by internationally recognised scientists. Specific chapters focus on the problems of administering drugs to animal airways, the mechanics of assessing lung function in the models, and describe in detail the species used, from rodents to primates. The use of genetically altered animals, an area of particular interest to molecular biologists, is also considered in depth. This up-to-date and extensively referenced work will prove invaluable to pharmacologists, physiologists and other biological scientists at all levels in academia and in the pharmaceutical industry.
Airway smooth muscle plays a dominant role in bronchial asthma, as well as a significant role in various pulmonary diseases, such as chronic bronchitis, cystic fibrosis and emphysema. Myogenic, neurogenic, and humoral factors control airway smooth-muscle tone. This text provides a state-of-the-art summary and critical discussion of airway smooth muscle from a multidisciplinary point of view. Topics discussed include morphology, biochemical regulation, mechanical and electrophysiological behavior and reflex control of smooth muscle; the epithelium-derived relaxing factor; and methods to measure smooth muscle function in vivo in humans and experimental animals, as well as in vitro in isolated airway tissues. Also discussed are calcium and potassium channels and receptors for adrenergic, cholinergic and histaminergic systems in modulating receptor-response coupling in airway smooth muscle. Airway Smooth Muscle: Modulation of Receptors and Response provides essential information for researchers, teachers, pulmonary specialists and allergists, and students interested in learning about airway smooth muscle.
I organized this book because there is a need to put together in book form recent advances in our knowledge of how airway smooth muscle:works in health and in disease. After a period when it seemed that progress was very slow, there has been in the past few years an incredibly rapid gathering of knowledge in this area. In particular, our understanding has improved regarding the cascades of events that follow the initial binding of agonist to plasma membrane receptors and that lead to the cross-bridge movements that determine contraction. This advance in our knowledge was stimulated by use of single-and whole-cell channel recordings of plasma membrane currents and by description of the l3-receptor-GTP-binding protein-adenylate cyclase-cAMP coupling system, which serves as a model for other coupling mechanisms. The discovery of the receptor-activated inositol phospholipid transduction system has greatly stimulated research and led to advances in our understanding of mechanisms involved in smooth muscle con traction. Major advances were also triggered by the development of indicators for measuring free cytosolic calcium concentration and starting the unraveling of 2 the events involved in Ca + -dependent activation of contractile proteins. Al though most of the studies that led to our current understanding of these areas were performed on nonairway smooth muscle, these studies usually add to our understanding of airway smooth muscle, and there is an enlarging body of data that have been obtained on airway smooth muscle.
Primarily, asthma is a disease of reversible airway constriction which is characterized by airways that constrict too easily and too much. These processes are modulated via a layer of airway smooth muscle (ASM) which surrounds each airway in the lung, wherein its activation leads to airway narrowing and potentially, closure. As a result, understanding the interaction between the ASM and the airway wall is crucial to understanding the reversible airway obstruction central to asthma. Although cross-bridge theory is a well-studied representation of complex smooth muscle dynamics, and can be coupled to the airway wall, this comes at significant computational cost, even for isolated airways. Because many phenomena of interest in pulmonary physiology cannot be adequately understood by studying isolated airways, this presents a significant limitation.We present a distribution moment (DM) approximation for the coupled system consisting of the ASM and the airway wall. Specifically, we first derive a reduced DM system for the cross-bridge theory which capture the macroscopic characteristics of the original full ASM theory. We then study the validity of the reduced coupled system when the airway is subjected to periodic pressure oscillations and show that in most cases, the DM system is valid. We also explore the region of breakdown. These results show that in many situations within physiological ranges, the DM approximation provides an orders-of-magnitude reduction in computational complexity relative to the full cross-bridge-airway coupled system. Deep inspirations (DI) are a widely studied topic due to their varied effectiveness as a bronchodilator in asthmatic and non-asthmatic patients. Specifically, it is known to be effective at reversing bronchoconstriction in non-asthmatic patients but may fail to prevent bronchoconstriction in asthmatic patients. Inspired by a recent study on the effect of deep inspirations on the rate of re-narrowing of an isolated airway, we investigate whether latch-bridge dynamics of the cross-bridge theory, coupled with non-linear compliance of the airway wall, can fully account for the reported results. We develop and present length-and pressure-controlled protocols which mimic both the experiments performed in the study, as well as simulate in vivo conditions respectively. The protocols are modelled using the DM approximation and show qualitative agreement with the results reported by the experiments, suggesting that latch-bridge dynamics coupled with airway wall non-compliance is sufficient to explain these results. As a secondary study, we also show that the DM approximated method is a suitable method to further investigate DIs on isolated (or branched) airways, as it is both qualitatively and quantitatively similar to the full cross-bridge model under equivalent conditions, and is less computationally intensive than traditional methods. We also study clustered ventilation defects, which are a hallmark of asthma characterized by the emergence of spatially organised regions of hypo- and hyper-ventilated airways.These regions (clusters) can vary from event to event and as such are considered to be partially dynamic rather than purely structural. We investigate these defects by incorporating rich ASM dynamics to systems of symmetrically branched coupled airways via the DM method, and compare the qualitative and quantitative behaviour of this system to a full ASM model, as well as to a simplified ASM model. We study the distribution of clusters of closed airways as a result of randomly perturbed initial airway radii for increasing ASM activation at static pressures. Our results show that the inclusion of rich ASM dynamics via the DM approximation leads to clustering distributions that are qualitatively similar to the highly simplified model as well as to the full ASM model. We also show that the DM model is less computationally intensive for both large and small numbers of coupled branched airways, and suggests that this model represents a viable option for the inclusion of rich ASM dynamics in whole lung models in future studies.
This landmark volume discusses the characteristics and impact of the remodeling process on airway function and clinical disease expression within the airway in asthma, covering pharmacological therapies and possible future targets relevant to regulating the remodeling process. Emphasizes the importance of treating underlying airway inflammation and the relevance of structural alterations to the airway wall, including glandular increases, enhanced collagen deposition within the submucosa, increased vasculature, smooth hypertrophy, and hyperplasias! Tracing the development and maintenance of bronchial hyperresponsiveness, decline in lung function, and loss of reversibility evident in chronic asthma, Airway Remodelingdescribes the contribution of inflammatory cells in the development of airway structural changes examines how pharmaceutical agents act and whether existing treatments modify or prevent remodeling in chronically inflamed asthmatic airways considers whether neural pathways initiate as well as contribute to the airway inflammatory cascade that leads to remodeling reviews the action of cytokines and growth factors on ASM signaling outlines novel approaches to regulating smooth muscle growth clarifies whether permanent ventilatory incapacity in asthma is caused by the uncoupling of the airway and the role of the lung parenchyma details high-resolution computerized tomography scan to measure the internal size of the airway at baseline, during challenge, or after bronchodilatation and more!Improving lung function and quality of life by reducing the need for emergency care, hospital admissions, and systemic steroid administration, Airway Remodeling is a superb reference for pulmonologists and respiratory system specialists; physiologists; pneumologists; allergists; pharmacologists; molecular, cellular, and lung biologists; and graduate and medical school students in these disciplines.
Asthma is a disease of high prevalence that has shown a trend toward increasing incidence, morbidity, and mortality over the last three decades despite apparently effective drug treatments and increasing awareness of the need for better disease management. Often the inflammatory component of asthma is studied; however, the tissue remodelling process is a significant process that should not be overlooked. This valuable reference synthesizes current data and concepts developed to determine the relationship between airway wall remodelling and the pathogenesis of asthma. It discusses evidence for structural changes in asthmatic airway, the relationship between airway thickening and hyperresponsiveness, the relationship between cytokine production and tissue remodelling and inflammation, the significance of epithelial changes and the extracellular matrix, and in vivo and in vitro experimental approaches to the assessment of remodelling. Pharmacological and biochemical mechanisms that control cell proliferation are also examined. The consequences of airway wall remodelling for airway hyperresponsiveness is the unique focus of this volume, offering a fresh perspective of advances in asthma research.
"The combination of scientific and institutional integrity represented by this book is unusual. It should be a model for future endeavors to help quantify environmental risk as a basis for good decisionmaking." â€"William D. Ruckelshaus, from the foreword. This volume, prepared under the auspices of the Health Effects Institute, an independent research organization created and funded jointly by the Environmental Protection Agency and the automobile industry, brings together experts on atmospheric exposure and on the biological effects of toxic substances to examine what is knownâ€"and not knownâ€"about the human health risks of automotive emissions.
