title: beta1-Integrins mediate enhancement of airway smooth muscle proliferation by collagen and fibronectin.
abstract: 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 beta1-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 alpha3 expression induced by PDGF-BB and monomeric type I collagen or fibronectin, alpha1, alpha2, alpha4, alpha5, alphav, and alphavbeta3 integrins were unchanged compared with unstimulated cells on plastic. Blocking antibodies revealed alpha2beta1- and alphavbeta3-mediated attachment to monomeric type I collagen, whereas attachment to fibronectin required alpha5beta1. In contrast, enhancement of PDGF-BB-dependent proliferation by either monomeric type I collagen or fibronectin required alpha2beta1, alpha4beta1, and alpha5beta1 integrins. These data suggest multiple beta1-integrins regulate enhanced ASM proliferative responses.
authors.affiliation: 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.
authors.forename: Trang T-B
authors.initials: TT
authors.lastname: Nguyen
authors.forename: Jeremy P T
authors.initials: JP
authors.lastname: Ward
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Hirst
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077214:Becaplermin; D001980:Bronchi / Q000166:cytology / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000494:pharmacology*; D024061:Collagen Type III / Q000494:pharmacology; D005260:Female; D005353:Fibronectins / Q000494:pharmacology*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000502:physiology; D039041:Integrin alpha4beta1 / Q000502:physiology; D039081:Integrin alpha5beta1 / Q000502:physiology; D039302:Integrin alphaVbeta3 / Q000502:physiology; D019012:Integrin beta1 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D019063:Tenascin / Q000494:pharmacology; D019096:Vitronectin / Q000494:pharmacology
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D005353:Fibronectins; D038982:Integrin alpha2beta1; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; D039302:Integrin alphaVbeta3; D019012:Integrin beta1; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D019063:Tenascin; D019096:Vitronectin; D000077214:Becaplermin