Functional consequences of human airway smooth muscle phenotype plasticity

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Abstract

BACKGROUND AND PURPOSE: Airway smooth muscle (ASM) phenotype plasticity, characterized by reversible switching between contractile and proliferative phenotypes, is considered to contribute to increased ASM mass and airway hyper-responsiveness in asthma. Further, increased expression of collagen I has been observed within the ASM bundle of asthmatics. Previously, we showed that exposure of intact bovine tracheal smooth muscle (BTSM) to collagen I induces a switch from a contractile to a hypocontractile, proliferative phenotype. However, the functional relevance of this finding for intact human ASM has not been established.

EXPERIMENTAL APPROACH: We investigated the effects of exposure of human tracheal smooth muscle (HTSM) strips to monomeric collagen I and PDGF on contractile responses to methacholine and KCl. Expression of contractile proteins sm-α-actin and sm-MHC was assessed by Western blot analysis. The proliferation of HTSM cells was assessed by cell counting, measuring mitochondrial activity (Alamarblue conversion) and [(3) H]-thymidine incorporation. Proliferation of intact tissue slices was assessed by [(3) H]-thymidine incorporation.

KEY RESULTS: Culturing HTSM strips in the presence of collagen I or PDGF for 4 days reduced maximal contractile responses to methacholine or KCl and the expression of contractile proteins. Conversely, collagen I and PDGF increased proliferation of HTSM cells and proliferative responses in tissue slices. PDGF additively increased the proliferation of HTSM cells cultured on collagen I; this additive effect was not observed on contractility, contractile protein expression or proliferation of intact tissue.

CONCLUSION AND IMPLICATIONS: These findings indicate that collagen I and PDGF induce a functionally hypocontractile, proliferative phenotype of human ASM, which may contribute to airway remodelling in asthma.

Original languageEnglish
Pages (from-to)359-367
Number of pages9
JournalBritish Journal of Pharmacology
Volume166
Issue number1
DOIs
Publication statusPublished - May-2012

Keywords

  • Actins
  • Blotting, Western
  • Cell Proliferation
  • Cells, Cultured
  • Collagen Type I
  • Humans
  • Methacholine Chloride
  • Myocytes, Smooth Muscle
  • Myosin Heavy Chains
  • Phenotype
  • Platelet-Derived Growth Factor
  • Potassium Chloride
  • Trachea

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