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Airway Epithelium in Atopic and Nonatopic Asthma: Similarities and Differences  [PDF]
Prathap Pillai,Chris J. Corrigan,Sun Ying
ISRN Allergy , 2011, DOI: 10.5402/2011/195846
Abstract: Asthma is an inflammatory disorder of the airways, and the airway epithelium has the central role in its pathogenesis. In general, the airway inflammation is characterised by the infiltration of the epithelium and submucosa by a range of inflammatory cells driven largely by Th-2 lymphocytes, eosinophils, and mast cells. The pathogenic mechanisms of nonatopic asthma in comparison to its atopic counterpart have always been a subject of debate. Although clinically are two distinct entities, more similarities than differences have been observed between the two in terms of immunopathogenesis, underlying IgE mechanisms, and so on. in a number of previous studies. More information has become available in recent years comparing the ultrastructure of the epithelium in these two types of asthma. A comparison of airway epithelium in atopic and nonatopic asthma is presented here from the available information in the literature. Similarities outnumber the differences, until we unravel the mystery surrounding these two important phenotypes of asthma in more detail. 1. Introduction Asthma is a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyper responsiveness, and underlying inflammation [1]. Asthma may be classified clinically on the basis of various parameters including the atopic status of the individual, the degree of airway obstruction, or the nature of trigger factors. By convention, the classification into atopic or nonatopic asthma is based on the presence or absence of clinical symptoms precipitated by one or more common aeroallergens, supported by the presence of allergen-specific antibodies as evidenced by skin prick +/? serological tests. The airways epithelium likely plays a key role in the pathogenesis of asthma, as it is a key interface with the external environment. There is ongoing debate as to whether atopic and nonatopic asthma are immunopathologically two distinct entities or if both are driven by similar mechanisms, and the answer to this question is still not clear. The entity of intrinsic or nonatopic asthma continues to raise questions about the possible role of IgE-mediated mechanisms in asthma pathogenesis. The clarification of this issue becomes more relevant with the current availability of anti-IgE therapy for the treatment of atopic asthma. The main theme of this paper is to address airway epithelium as central to the theatre of asthmatic inflammation and to compare the airways microenvironment in atopic and nonatopic asthma. 2. Airway Epithelium
Cultured Human Airway Epithelial Cells (Calu-3): A Model of Human Respiratory Function, Structure, and Inflammatory Responses  [PDF]
Yan Zhu,Aaron Chidekel,Thomas H. Shaffer
Critical Care Research and Practice , 2010, DOI: 10.1155/2010/394578
Abstract: This article reviews the application of the human airway Calu-3 cell line as a respiratory model for studying the effects of gas concentrations, exposure time, biophysical stress, and biological agents on human airway epithelial cells. Calu-3 cells are grown to confluence at an air-liquid interface on permeable supports. To model human respiratory conditions and treatment modalities, monolayers are placed in an environmental chamber, and exposed to specific levels of oxygen or other therapeutic modalities such as positive pressure and medications to assess the effect of interventions on inflammatory mediators, immunologic proteins, and antibacterial outcomes. Monolayer integrity and permeability and cell histology and viability also measure cellular response to therapeutic interventions. Calu-3 cells exposed to graded oxygen concentrations demonstrate cell dysfunction and inflammation in a dose-dependent manner. Modeling positive airway pressure reveals that pressure may exert a greater injurious effect and cytokine response than oxygen. In experiments with pharmacological agents, Lucinactant is protective of Calu-3 cells compared with Beractant and control, and perfluorocarbons also protect against hyperoxia-induced airway epithelial cell injury. The Calu-3 cell preparation is a sensitive and efficient preclinical model to study human respiratory processes and diseases related to oxygen- and ventilator-induced lung injury. 1. Introduction The airway epithelial is involved in the pathogenesis and treatment of many lung diseases, including adult and neonatal respiratory distress syndrome (RDS), chronic obstructive pulmonary disease (COPD), asthma, the adverse effects of positive pressure mechanical ventilation [1–4], and supplemental oxygen therapy [5]. The airway epithelium is directly exposed to the external environment and is highly responsive to biophysical and biological stimuli. Via a variety of cellular pathways and mechanisms, the respiratory epithelium responds to exogenous substances, stresses, or medical therapies that may promote airway repair or injury. Understanding the role of the airway epithelium and its response to injurious stimuli, therapeutic drugs, and interventions will aid in determining the mechanisms of airway injury and should facilitate the development of novel therapies for lung diseases. This experimental approach is one component of a robust approach to assess multiple aspects of respiratory pathophysiology. With the inherent difficulties of primary human lung cell culture and the limit of whole-animal studies, in vitro
Responses of Airway Epithelium to Environmental Injury: Role in the Induction Phase of Childhood Asthma  [PDF]
Rakesh K. Kumar,Jessica S. Siegle,Gerard E. Kaiko,Cristan Herbert,Joerg E. Mattes,Paul S. Foster
Journal of Allergy , 2011, DOI: 10.1155/2011/257017
Abstract: The pathogenesis of allergic asthma in childhood remains poorly understood. Environmental factors which appear to contribute to allergic sensitisation, with development of a Th2-biased immunological response in genetically predisposed individuals, include wheezing lower respiratory viral infections in early life and exposure to airborne environmental pollutants. These may activate pattern recognition receptors and/or cause oxidant injury to airway epithelial cells (AECs). In turn, this may promote Th2 polarisation via a “final common pathway” involving interaction between AEC, dendritic cells, and CD4+ T lymphocytes. Potentially important cytokines produced by AEC include thymic stromal lymphopoietin and interleukin-25. Their role is supported by in vitro studies using human AEC, as well as by experiments in animal models. To date, however, few investigations have employed models of the induction phase of childhood asthma. Further research may help to identify interventions that could reduce the risk of allergic asthma. 1. Introduction Asthma is one of the most common chronic diseases affecting children, especially in economically developed nations. For example, in Australia the prevalence of current asthma in children aged 0–15 years is approximately 11% [1]. Childhood asthma is strongly linked to atopy, which in turn is characteristically associated with a Th2-biased immunological response [2–4]. While this relationship is well documented, the pathogenesis of childhood asthma remains largely unexplained. However, it is clear that both genetic predisposition and a variety of environmental factors contribute to the development of allergic asthma [4]. Notable among the environmental factors that appear to be crucial in the induction of disease is respiratory viral infection, in particular with rhinovirus (RV) or respiratory syncytial virus (RSV). The association between childhood infections and asthma is complex, because at least in some settings, repeated early-life exposure to infectious agents may reduce the likelihood of developing allergic diseases [5]. Despite this, epidemiological studies strongly suggest that lower respiratory viral infections associated with wheezing, occurring within a critical period of development in early childhood, play an important role in the subsequent development of asthma in children who are repeatedly exposed to inhaled allergens [6–10]. Another clearly defined risk factor for childhood allergic asthma is early-life exposure to airborne environmental irritants. The importance of exposure to environmental tobacco smoke
Are mouse models of asthma appropriate for investigating the pathogenesis of airway hyper-responsiveness?  [PDF]
Rakesh K. Kumar
Frontiers in Physiology , 2012, DOI: 10.3389/fphys.2012.00312
Abstract: Whether mouse models of chronic asthma can be used to investigate the relationship between airway inflammation/remodeling and airway hyper-responsiveness (AHR) is a vexed question. It raises issues about the extent to which such models replicate key features of the human disease. Here, we review some of the characteristic pathological features of human asthma and their relationship to AHR and examine some limitations of mouse models that are commonly used to investigate these relationships. We compare these conventional models with our mouse model of chronic asthma involving long-term low-level inhalational challenge and review studies of the relationship between inflammation/remodeling and AHR in this model and its derivatives, including models of an acute exacerbation of chronic asthma and of the induction phase of childhood asthma. We conclude that while extrapolating from studies in mouse models to AHR in humans requires cautious interpretation, such experimental work can provide significant insights into the pathogenesis of airway responsiveness and its molecular and cellular regulation.
In Vivo Disruption of TGF-β Signaling by Smad7 in Airway Epithelium Alleviates Allergic Asthma but Aggravates Lung Carcinogenesis in Mouse  [PDF]
Xiaolin Luo,Qiurong Ding,Min Wang,Zhigang Li,Kairui Mao,Bing Sun,Yi Pan,Zhenzhen Wang,Ying Qin Zang,Yan Chen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010149
Abstract: TGF-β has been postulated to play an important role in the maintenance of epithelial homeostasis and the development of epithelium-derived cancers. However, most of previous studies are mainly focused on the function of TGF-β in immune cells to the development of allergic asthma and how TGF-β signaling in airway epithelium itself in allergic inflammation is largely unknown. Furthermore, the in vivo TGF-β function specifically in the airway epithelium during lung cancer development has been largely elusive.
Inflammation signals airway smooth muscle cell proliferation in asthma pathogenesis  [cached]
Khan Mohammad Afzal
Multidisciplinary Respiratory Medicine , 2013, DOI: 10.1186/2049-6958-8-11
Abstract: Background Airway inflammation stimulates proliferation of airway smooth muscle cell, which contributes to the development of hyperplasia and hypertrophy of smooth muscle cell. The increase in airway smooth muscle cell mass is believed to be due to an up-regulation of inflammatory mediators in the airway. It is now well recognized that chronic inflammation as well as airway hyper-responsiveness and remodeling of airway during inflammation, are crucial to asthma. Airway hyper-responsiveness is caused by increased cell proliferation or by hypertrophy of airway smooth muscle cell depending on the nature of the inflammatory stimulation. Airway smooth muscle cell proliferation in asthma is regulated by the proinflammatory cytokines including IL-1β and TNF-α. These proinflammatory cytokines have been shown to influence human airway smooth muscle cell proliferation in vitro, which is due to cyclooxygenase-2 expression, production of prostaglandin E2, and increased cAMP levels. Conclusions This review highlights the role of different proinflammatory cytokines in regulating airway smooth muscle cell growth and also focuses on regulation of differential gene expression in airway smooth muscle cell by growth factors and cytokines, also to bestow unique insight into the effects of conventional asthma therapies on airway smooth muscle cell proliferation and development of new therapeutic strategies to control asthma.
Neuronal Modulation of Airway and Vascular Tone and Their Influence on Nonspecific Airways Responsiveness in Asthma  [PDF]
Brendan J. Canning,Ariel Woo,Stuart B. Mazzone
Journal of Allergy , 2012, DOI: 10.1155/2012/108149
Abstract: The autonomic nervous system provides both cholinergic and noncholinergic neural inputs to end organs within the airways, which includes the airway and vascular smooth muscle. Heightened responsiveness of the airways to bronchoconstrictive agents is a hallmark feature of reactive airways diseases. The mechanisms underpinning airways hyperreactivity still largely remain unresolved. In this paper we summarize the substantial body of evidence that implicates dysfunction of the autonomic nerves that innervate smooth muscle in the airways and associated vasculature as a prominent cause of airways hyperresponsiveness in asthma. 1. Introduction With the exception of airway smooth muscle, perhaps no other group of cells has as clear a role in the pathogenesis of asthma as the neurons comprising the afferent and efferent innervation of the airways and lungs. The symptoms of asthma—wheezing, dyspnea, chest tightness, cough, reversible airways obstruction, mucus hypersecretion, and airways hyperresponsiveness—all inextricably link the nervous system to this disease. It is thus remarkable that in the 440 pages of the National Heart, Lung and Blood Institute (NHLBI) guidelines on asthma, nerves are mentioned in just one sentence [1]. Nerves are not mentioned at all in the British Thoracic Society (BTS) guidelines for asthma [2]. Even the recent and potentially landmark study by Peters et al. [3], in which the anticholinergic tiotropium was found to be at least as good as steroids or β-agonists (perhaps better) for treatment of asthma, nerves are not mentioned in the article itself nor in the accompanying editorial [4]. In this brief review we summarize the large body of evidence supporting a primary role for airway autonomic nerve dysfunction in the hyperresponsiveness of the airway smooth muscle in asthma. 2. The Understated Role of Nerves in Asthma Guidelines such as those produced by the NHLBI and BTS, in which immune cells including eosinophils are given a central role in asthma pathogenesis appropriately highlight the prominent feature of inflammation in the asthmatic lung. Inflammation may precipitate airways hyperresponsiveness [1, 5–8]. But the association between inflammation and airways hyperresponsiveness has probably been overemphasized [9–13]. The bias towards inflammation in asthma guidelines reveals the disproportionate influence immunologists, and allergists have had overdefining this disease for national and international medical organizations as well as their influence over the direction of asthma-related research. As asthma prevalence and asthma
Mitochondrial Dysfunction and Oxidative Stress in Asthma: Implications for Mitochondria-Targeted Antioxidant Therapeutics  [PDF]
P. Hemachandra Reddy
Pharmaceuticals , 2011, DOI: 10.3390/ph4030429
Abstract: Asthma is a complex, inflammatory disorder characterized by airflow obstruction of variable degrees, bronchial hyper-responsiveness, and airway inflammation. Asthma is caused by environmental factors and a combination of genetic and environmental stimuli. Genetic studies have revealed that multiple loci are involved in the etiology of asthma. Recent cellular, molecular, and animal-model studies have revealed several cellular events that are involved in the progression of asthma, including: increased Th2 cytokines leading to the recruitment of inflammatory cells to the airway, and an increase in the production of reactive oxygen species and mitochondrial dysfunction in the activated inflammatory cells, leading to tissue injury in the bronchial epithelium. Further, aging and animal model studies have revealed that mitochondrial dysfunction and oxidative stress are involved and play a large role in asthma. Recent studies using experimental allergic asthmatic mouse models and peripheral cells and tissues from asthmatic humans have revealed antioxidants as promising treatments for people with asthma. This article summarizes the latest research findings on the involvement of inflammatory changes, and mitochondrial dysfunction/oxidative stress in the development and progression of asthma. This article also addresses the relationship between aging and age-related immunity in triggering asthma, the antioxidant therapeutic strategies in treating people with asthma.
Immunolocalization of NLRP3 Inflammasome in Normal Murine Airway Epithelium and Changes following Induction of Ovalbumin-Induced Airway Inflammation  [PDF]
Hai B. Tran,Martin D. Lewis,Lor Wai Tan,Susan E. Lester,Leonie M. Baker,Jia Ng,Monica A. Hamilton-Bruce,Catherine L. Hill,Simon A. Koblar,Maureen Rischmueller,Richard E. Ruffin,Peter J. Wormald,Peter D. Zalewski,Carol J. Lang
Journal of Allergy , 2012, DOI: 10.1155/2012/819176
Abstract: Little is known about innate immunity and components of inflammasomes in airway epithelium. This study evaluated immunohistological evidence for NLRP3 inflammasomes in normal and inflamed murine (Balb/c) airway epithelium in a model of ovalbumin (OVA) induced allergic airway inflammation. The airway epithelium of control mice exhibited strong cytoplasmic staining for total caspase-1, ASC, and NLRP3, whereas the OVA mice exhibited strong staining for active caspase-1, with redistribution of caspase-1, IL-1β and IL-18, indicating possible activation of the NLRP3 inflammasome. Active caspase-1, NLRP3, and other inflammasome components were also detected in tissue eosinophils from OVA mice, and may potentially contribute to IL-1β and IL-18 production. In whole lung, inRNA expression of NAIP and procaspase-1 was increased in OVA mice, whereas NLRP3, IL-1β and IL-18 decreased. Some OVA-treated mice also had significantly elevated and tightly correlated serum levels of IL-1β and TNFα. In cultured normal human bronchial epithelial cells, LPS priming resulted in a significant increase in NLRP3 and II-lp protein expression. This study is the first to demonstrate NLRP3 inflammasome components in normal airway epithelium and changes with inflammation. We propose activation and/or luminal release of the inflammasome is a feature of allergic airway inflammation which may contribute to disease pathogenesis. 1. Introduction Asthma affects up to 12% of adults and 25% of children in Australia and there is a significant undiagnosed cohort [1]. Although we have a range of medications that are effective in their own right, there is a need to further improve the management of this disease. This involves better clinical programs and an improved understanding of the basic mechanisms of asthma so that new ways can be introduced which work synergistically with conventional asthma medications to modify airway inflammation. Asthma is a disease characterized by both bronchiolar smooth muscle constriction and a chronic airway inflammation. Some of the features of the disease are modelled in the well-characterized acute and chronic models of OVA-induced allergic airway inflammation in mice [2, 3]. The inflammatory component of asthma is generally thought of as a Th2-driven process, involving eosinophil recruitment to the airways and consequent damage, including airway epithelial cell death [4]. Damage and repair eventually lead to a remodelling of the airways which increases the sensitivity of the airway muscle to cholinergic agonists and further restricts airflow. However, other
Mitochondrial Dysfunction in Metabolic Syndrome and Asthma  [PDF]
Ulaganathan Mabalirajan,Balaram Ghosh
Journal of Allergy , 2013, DOI: 10.1155/2013/340476
Abstract: Though severe or refractory asthma merely affects less than 10% of asthma population, it consumes significant health resources and contributes significant morbidity and mortality. Severe asthma does not fell in the routine definition of asthma and requires alternative treatment strategies. It has been observed that asthma severity increases with higher body mass index. The obese-asthmatics, in general, have the features of metabolic syndrome and are progressively causing a significant burden for both developed and developing countries thanks to the westernization of the world. As most of the features of metabolic syndrome seem to be originated from central obesity, the underlying mechanisms for metabolic syndrome could help us to understand the pathobiology of obese-asthma condition. While mitochondrial dysfunction is the common factor for most of the risk factors of metabolic syndrome, such as central obesity, dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, the involvement of mitochondria in obese-asthma pathogenesis seems to be important as mitochondrial dysfunction has recently been shown to be involved in airway epithelial injury and asthma pathogenesis. This review discusses current understanding of the overlapping features between metabolic syndrome and asthma in relation to mitochondrial structural and functional alterations with an aim to uncover mechanisms for obese-asthma. 1. Introduction Mitochondria, dynamic organelles assumed to be originated from α-proteobacteria, not only generate energy in the form of ATP but also regulate numerous cellular functions relevant to cell fate, such as apoptosis, generation of oxidative free radicals, and calcium homeostasis [1]. Every mitochondrion has 2 membranous and 2 aqueous compartments: outer membrane, intermembranous space, inner membrane, and matrix [2]. Outer membrane contains numerous porins which form channels through which solutes (≤5000 Daltons) enter freely inside the mitochondria. In contrast, it specifically permits larger mitochondria-targeting signal peptide containing pre-proteins which interact with translocase of outer membrane complex [3]. Mitochondrial intermembranous space, one of the aqueous compartments, contains small molecules which are very similar to cytosol, protein components which vary from cytosol thanks to the restricted entry of larger proteins through outer membrane and protons from oxidative phosphorylation [4]. The inner membrane of mitochondria is folded to form enormous cristae to increase the surface area and to enhance the ATP generating
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