Functional consequences of human airway smooth muscle phenotype plasticity

• Published in: British journal of pharmacology Vol. 166; no. 1; pp. 359 - 367
• Main Authors: Dekkers, Bart GJ, Bos, I Sophie T, Zaagsma, Johan, Meurs, Herman
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-05-2012; Nature Publishing Group
• Subjects: Actins - metabolism; airway smooth muscle contractility; airway smooth muscle proliferation; Asthma; Biological and medical sciences; Blotting, Western; Cell Proliferation - drug effects; Cells, Cultured; Collagen; collagen type I; Collagen Type I - pharmacology; Genotype & phenotype; Humans; Medical sciences; Methacholine Chloride - pharmacology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myosin Heavy Chains - metabolism; Pharmacology. Drug treatments; Phenotype; phenotype modulation; Platelet-Derived Growth Factor - pharmacology; platelet‐derived growth factor; Potassium Chloride - pharmacology; Research Papers; Smooth muscle; Trachea - cytology; Trachea - drug effects; Trachea - metabolism; Human; Cell proliferation; Contractility; Smooth muscle; platelet-derived growth factor; Respiratory system; Respiratory tract; Phenotype; Collagen type I; airway smooth muscle proliferation; Plasticity; airway smooth muscle contractility; phenotype modulation; Platelet derived growth factor
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01773.x

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 [3H]‐thymidine incorporation. Proliferation of intact tissue slices was assessed by [3H]‐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.