title: Laminin drives survival signals to promote a contractile smooth muscle phenotype and airway hyperreactivity.
abstract: Increased airway smooth muscle (ASM) mass is believed to underlie the relatively fixed airway hyperresponsiveness (AHR) in asthma. Developments of therapeutic approaches to reverse airway remodeling are impeded by our lack of insight on the mechanisms behind the increase in mass of contractile ASM cells. Increased expression of laminin, an extracellular matrix protein, is associated with asthma. Our studies investigate the role of laminin-induced ASM survival signals in the development of increased ASM and AHR. Antagonizing laminin integrin binding using the laminin-selective competing peptide, YIGSR, and mimicking laminin with exogenous α2-chain laminin, we show that laminin is both necessary and sufficient to induce ASM cell survival, concomitant with the induction of ASM contractile phenotype. Using siRNA, we show that the laminin-binding integrin α7β1 mediates this process. Moreover, in laminin-211-deficient mice, allergen-induced AHR was not observed. Notably, ASM cells from asthmatic airways express a higher abundance of intracellular cell survival proteins, consistent with a role for reduced rates of cell apoptosis in development of ASM hyperplasia. Targeting the laminin-integrin α7β1 signaling pathway may offer new avenues for the development of therapies to reduce the increase in mass of contractile phenotype ASM cells that underlie AHR in asthma.
authors.affiliation: 2Department of Physiology, National University of Singapore, Block MD9, 2 Medical Dr., Singapore 117597. E-Mail: tran_thai@nuhs.edu.sg.
authors.forename: Thai
authors.initials: T
authors.lastname: Tran
authors.forename: Chun Ming
authors.initials: CM
authors.lastname: Teoh
authors.forename: John Kit Chung
authors.initials: JK
authors.lastname: Tam
authors.forename: Yongkang
authors.initials: Y
authors.lastname: Qiao
authors.forename: Chin Yein
authors.initials: CY
authors.lastname: Chin
authors.forename: Oi Khuan
authors.initials: OK
authors.lastname: Chong
authors.forename: Alastair G
authors.initials: AG
authors.lastname: Stewart
authors.forename: Trudi
authors.initials: T
authors.lastname: Harris
authors.forename: Wai Shiu Fred
authors.initials: WS
authors.lastname: Wong
authors.forename: Shou Ping
authors.initials: SP
authors.lastname: Guan
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Leung
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
authors.forename: Helmut
authors.initials: H
authors.lastname: Unruh
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D015415:Biomarkers; D016535:Bronchial Hyperreactivity / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D005260:Female; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D007797:Laminin / Q000378:metabolism* / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D010047:Ovalbumin / Q000276:immunology; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology*; D013873:Thionucleotides / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D015415:Biomarkers; D016023:Integrins; D007797:Laminin; D034741:RNA, Small Interfering; D013873:Thionucleotides; D051028:bcl-2-Associated X Protein; C408162:oblimersen; D010047:Ovalbumin; C082908:integrin alpha7beta1
keywords: apoptosis; integrin; phenotype plasticity