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Major role of the extracellular matrix in airway smooth muscle phenotype plasticity : implications for chronic asthma

By Bart Gerrit Jan Dekkers

Abstract

Allergic asthma is a chronic inflammatory airway disease, characterized by increased responsiveness of the airways to a variety of bronchial obstructive stimuli. This airway hyperresponsiveness is importantly determined by alterations in the airway wall, including increased airway smooth muscle (ASM) mass and -contractility and changes in the extracellular matrix (ECM). The present thesis describes the effects of various ECM proteins on ASM function in relation to the pathophysiology of asthma. It was demonstrated that the ECM proteins collagen I and fibronectin, like growth factors such as platelet-derived growth factor (PDGF), induced a proliferative, hypocontractile ASM phenotype, characterized by increased cell proliferation and decreased contractility of the muscle. This is caused by interaction with specific integrin receptors on the ASM cell and subsequent activation of integrin-coupled intracellular signalling cascades. Conversely, laminin-111 and laminin-211 induced a (hyper)contractile and hypoproliferative phenotype. The effects of collagen I and PDGF on ASM function were effectively and synergistically inhibited by a combination of glucocorticosteroids and 2-agonists, the cornerstone of current asthma therapy. Interestingly, this combination prevented glucocorticosteroid resistance induced by collagen I. In a guinea pig model of chronic allergic asthma, allergen-induced increased ASM mass and contractility were prevented by inhalation of the peptide arginine-glycine-aspartic acid-serine (RGDS), which antagonizes the interaction of above-mentioned ECM proteins with specific arginine-glycine-aspartic acid (RGD)-binding integrins. These results for the first time demonstrate that ECM proteins importantly contribute to ASM changes in asthma. Moreover, peptides with the RGD motif may represent an interesting novel therapeutic approach for the treatment of asthma.

Topics: Glucocorticosteroïden, Integrinen; Spiercontracties; Laminine; Extracellulaire matrix; Fenotypische plasticiteit; Gladde spieren; Astma; Adrenergische geneesmiddelen; Proefschriften (vorm); thorax
Year: 2010
OAI identifier: oai:ub.rug.nl:dbi/4c08f165cad0f
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