Epithelial-mesenchymal interactions in the pathogenesis of asthma (original) (raw)
Related papers
The airway epithelium dysfunction in the pathogenesis of asthma: The evidence
Health, 2013
Asthma is traditionally defined as a chronic, multisystem, multicellular disease characterized by bronchial hyper-responsiveness (BHR) and lung inflammation. In this illness is particularly involving the airway epithelium as the place where the inflammation begins, develops and often returns through airway remodelling. In specific way there is also an evolving awareness of the active participation of structural elements, such as the airway epithelium, airway smooth muscle, and endothelium, in this process. The airway inflammation and remodelling together likely explain the clinical manifestations of asthma that is demonstrated by complicated respiratory manifestations in which wheeze occurring secondary to bronchoconstriction in the setting of airway hyper-responsiveness and mucous hypersecretion. This is confirmed by also the histopathological analyses of bronchial biopsies from asthmatic subjects. For this reason is very important to understand the physiological role of the airway epithelium and their changes during the exacerbation of disease.
New Insights into Asthma Pathogenesis
Allergy & Clinical Immunology International - Journal of the World Allergy Organization, 2004
Although Th-2-mediated inflammation is a key therapeutic target in asthma, its relationship to altered structure and functions of the airways is largely unknown. In addition to inflammation, asthma is a disorder involving the airway epithelium that is more vulnerable to environmental injury and responds to this by impaired healing. This establishes a chronic wound scenario that is capable of sustaining chronic inflammation as well as remodeling. This response occurs as a consequence of activation of the epithelial-mesenchymal unit, involving reciprocal activities of growth factors belonging to the fibroblast growth factor, epidermal growth factor, and transforming growth factor- families. The observation that structural changes in the airways in children at or before the onset of asthma occurs irrespective of inflammation might suggest that premodeling is required before Th-2 inflammatory responses can be sustained. Once established, altered function of constitutive airway cells, including fibroblasts, smooth muscle, nerves, and the epithelium, provides an abnormal microenvironment in which to generate a separate set of signals that underpin the acute/subacute inflammation characteristic of asthma exacerbations, triggered by viruses, pollutants, and allergens.
Medicine, 2008
asthma is a syndrome of variable airflow obstruction. it is character ized pathologically by bronchial inflammation with prominent eosinophil infiltration and remodelling changes, physiologically by bronchial hyper responsiveness, and clinically by cough, chest tightness and wheeze. cytokines secreted by cD4+ th2 type t cells play a major role in co ordinating asthmatic bronchial inflammation and remodelling, while other effector cells, particularly eosinophils and myofibroblasts, play an intermediary role in airways damage and remodelling. although the patho logical changes in the airways in association with asthma are now well described, there is a gap in our understanding of precisely how these changes cause clinical symptoms. a key aetiological factor for asthma is exposure to inhaled allergens, including occupational allergens, which are probably a major drive to t cell activation in asthma. Genetic factors governing the production of t cell cytokines and their actions on target cells, as well as variability in the structure and development of the mesenchymal elements of the bronchial mucosa, influence the risk of developing asthma. many other environmental agents exacerbate asthma but the evidence that they cause disease is much less clear.
The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma
Clinical <html_ent glyph="@amp;" ascii="&"/> Experimental Allergy, 1999
While asthma is an inflammatory disorder of the airways involving mediator release from mast cells and eosinophils and orchestrated by T cells, inflammation alone is insufficient to explain the chronic nature of the disease and its progression. Evidence is presented that the epithelium is fundamentally disordered in chronic asthma manifest by increased fragility, and an altered phenotype to one that secretes mucus, mediators, cytokines, chemokines and growth factors. Epithelial injury is mediated by exogenous factors such as air pollutants, viruses and allergens as well as by endogenous factors including the release of proteolytic enzymes from mast cells (tryptase, chymase) and eosinophils (MMP-9). Following injury, the normal epithelium should respond with increased proliferation driven by ligands acting on epidermal growth factor (EGF) receptors or through transactivation of the receptor. The epithelial response to these stimuli in asthma appears to be impaired despite upregulation of CD44 capable of enhancing presentation of EGF ligands to epidermal growth factor receptors (EGFR). Because the epithelium is 'held' in this repair phenotype, it becomes a continuous source of proinflammatory products as well as growth factors that drive airway wall remodelling.
Journal of Allergy and Clinical Immunology, 2011
Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways. Airway remodeling in asthmatic patients involves a wide array of pathophysiologic features, including epithelial changes, increased smooth muscle mass, increased numbers of activated fibroblasts/myofibroblasts, subepithelial fibrosis, and vascular changes. Multiple cytokines, chemokines, and growth factors released from both inflammatory and structural cells in the airway tissue create a complex signaling environment that drives these structural changes. However, recent investigations have changed our understanding of asthma from a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Several reports have suggested that asthma primarily develops because of serious defects in the epithelial layer that allow environmental allergens, microorganisms, and toxins greater access to the airway tissue and that can also stimulate the release of mediators from the epithelium, thus contributing to tissue remodeling. Lung-resident fibroblasts and smooth muscle cells have also been implicated in the pathogenesis of airway remodeling. Remodeling is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness. Asthmatic subjects experience an accelerated decrease in lung function compared with healthy subjects, which is proportionally related to the duration and severity of their disease.
Epithelial-mesenchymal communication in the pathogenesis of chronic asthma
Proceedings of the American Thoracic Society, 2004
Although Th-2-mediated inflammation is a key therapeutic target in asthma, its relationship to altered structure and functions of the airways is largely unknown. In addition to inflammation, asthma is a disorder involving the airway epithelium that is more vulnerable to environmental injury and responds to this by impaired healing. This establishes a chronic wound scenario that is capable of sustaining chronic inflammation as well as remodeling. This response occurs as a consequence of activation of the epithelial-mesenchymal unit, involving reciprocal activities of growth factors belonging to the fibroblast growth factor, epidermal growth factor, and transforming growth factor-beta families. The observation that structural changes in the airways in children at or before the onset of asthma occurs irrespective of inflammation might suggest that premodeling is required before Th-2 inflammatory responses can be sustained. Once established, altered function of constitutive airway cells...
New insights into the pathogenesis of asthma
Journal of Clinical Investigation, 2003
Asthma is a disease whose ability to cause episodic symptomatology has been appreciated since antiquity. Although the fine points of the definition can be debated, it is reasonable to think of asthma as a pulmonary disorder characterized by the generalized reversible obstruction of airflow and to define reversibility as a greater than 12% increase in the patient's forced expiratory volume in 1 second (FEV 1 ) that occurs either spontaneously or with therapy. Airway hyperresponsiveness, an exaggerated bronchospastic response to nonspecific agents such as methacholine and histamine or specific antigens, is the physiologic cornerstone of this disorder. A diagnosis of asthma is established based on a history of recurrent wheeze, cough, or shortness of breath, reversible airway obstruction demonstrated by pulmonary-function testing, and, in cases where questions exist, a methacholine challenge demonstrating airway hyperresponsiveness. It has long been assumed that patients with asthma experience intermittent attacks and have relatively normal lung function during intervening periods. More recent studies have demonstrated that asthma can cause progressive lung impairment and, in some patients, eventuate in partially reversible or irreversible airway obstruction.
Invited Lecture: Activation of the Epithelial Mesenchymal Trophic Unit in the Pathogenesis of Asthma
International Archives of Allergy and Immunology, 2001
Background: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. Methods: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. Results: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme – the epithelial mesenchymal trophic unit – leading to disease persistence, airway remodelling and refractoriness to corticosteroid trea...