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ß1-Integrins Mediate Enhancement of Airway Smooth Muscle Proliferation by Collagen and Fibronectin

Department of Asthma, Allergy and Respiratory Science, The Guy's, King's, and St. Thomas' School of Medicine, King's College London, Guy's Hospital Campus, London, United Kingdom

Correspondence and requests for reprints should be addressed to Stuart J. Hirst, Ph.D., Department of Asthma, Allergy & Respiratory Science, The Guy's, King's, and St. Thomas' School of Medicine, Thomas Guy House, Guy's Hospital Campus, London SE1 9RT, UK. E-mail: stuart.hirst{at}kcl.ac.uk

Airway smooth muscle (ASM) accumulation and enrichment of the extracellular matrix (ECM) with type I collagen and fibronectin are major pathologic features of airway remodeling in asthma. These ECM components confer enhanced ASM proliferation in vitro, but a requirement for specific integrin ECM receptors has not been examined. Here, we examined the mitogen platelet-derived growth factor (PDGF)-BB on ß1-integrin expression on human ASM cells cultured on these ECM substrates and defined the involvement of specific integrins in cell attachment and proliferation using integrin-neutralizing antibodies. PDGF-BB–dependent proliferation was enhanced two- to threefold by monomeric type I collagen or fibronectin and to a lesser extent by vitronectin; other interstitial ECM components (fibrillar type I and III collagen and tenascin-C) had no effect. Except for increased 3 expression induced by PDGF-BB and monomeric type I collagen or fibronectin, 1, 2, 4, 5, v, and vß3 integrins were unchanged compared with unstimulated cells on plastic. Blocking antibodies revealed 2ß1- and vß3-mediated attachment to monomeric type I collagen, whereas attachment to fibronectin required 5ß1. In contrast, enhancement of PDGF-BB–dependent proliferation by either monomeric type I collagen or fibronectin required 2ß1, 4ß1, and 5ß1 integrins. These data suggest multiple ß1-integrins regulate enhanced ASM proliferative responses.

Key Words: airway remodeling • airway smooth muscle • extracellular matrix • integrin • proliferation

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