Abstract
BackgroundFibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. In vitro studies have shown that maturation of ASM cells to a (hyper)contractile phenotype is dependent on laminin, which can be inhibited by the laminin-competing peptide Tyr-Ile-Gly-Ser-Arg (YIGSR). The role of laminins in ASM remodelling in chronic asthma in vivo, however, has not yet been established.MethodsUsing an established guinea pig model of allergic asthma, we investigated the effects of topical treatment of the airways with YIGSR on features of airway remodelling induced by repeated allergen challenge, including ASM hyperplasia and hypercontractility, inflammation and fibrosis. Human ASM cells were used to investigate the direct effects of YIGSR on ASM proliferation in vitro.ResultsTopical administration of YIGSR attenuated allergen-induced ASM hyperplasia and pulmonary expression of the proliferative marker proliferating cell nuclear antigen (PCNA). Treatment with YIGSR also increased both the expression of sm-MHC and ASM contractility in saline- and allergen-challenged animals; this suggests that treatment with the laminin-competing peptide YIGSR mimics rather than inhibits laminin function in vivo. In addition, treatment with YIGSR increased allergen-induced fibrosis and submucosal eosinophilia. Immobilized YIGSR concentration-dependently reduced PDGF-induced proliferation of cultured ASM to a similar extent as laminin-coated culture plates. Notably, the effects of both immobilized YIGSR and laminin were antagonized by soluble YIGSR.ConclusionThese results indicate that the laminin-competing peptide YIGSR promotes a contractile, hypoproliferative ASM phenotype in vivo, an effect that appears to be linked to the microenvironment in which the cells are exposed to the peptide.
Highlights
Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma
Repeated ovalbumin challenge did not change the number of nuclei per mm2 of smooth muscle area (Figure 1B), indicating that the cell size is unchanged and ovalbumin-induced increases in ASM mass were caused by increased cell number
YIGSR treatment did not change ASM cell size in saline-challenged animals; a small, but significant (P < 0.05) decrease in the number of nuclei/mm2 was observed in ovalbumin-challenged animals (Figure 1B), suggesting that this treatment may lead to some increase in cell size
Summary
Fibroproliferative airway remodelling, including increased airway smooth muscle (ASM) mass and contractility, contributes to airway hyperresponsiveness in asthma. Structural changes in the airway wall are thought to contribute to a decline of lung function and development of persistent airway hyperresponsiveness in chronic asthma [1,3]. For example by serum deprivation in the presence of insulin, results in maturation of the cells to a contractile phenotype, characterized by increased expression of contractile protein markers, increased contractile function and increased expression of laminin a2, b1 and g1 chains [8,13,14,15]. Expression of laminin a2 and b2 chains in the airways is increased [18,19]. Asthmatics with compromised epithelial integrity show increased laminin g2 chain expression in the airways [19]
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