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Mast Cells Promote Airway Smooth Muscle Cell Differentiation via Autocrine Up-Regulation of TGF-β1¹

Institute for Lung Health, Department of Infection, Inflammation and Immunity, University of Leicester, Leicester, United Kingdom

Asthma is a major cause of morbidity and mortality worldwide. It is characterized by airway dysfunction and inflammation. A key determinant of the asthma phenotype is infiltration of airway smooth muscle bundles by activated mast cells. We hypothesized that interactions between these cells promotes airway smooth muscle differentiation into a more contractile phenotype. In vitro coculture of human airway smooth muscle cells with β-tryptase, or mast cells with or without IgE/anti-IgE activation, increased airway smooth muscle-derived TGF-β1 secretion, -smooth muscle actin expression and agonist-provoked contraction. This promotion to a more contractile phenotype was inhibited by both the serine protease inhibitor leupeptin and TGF-β1 neutralization, suggesting that the observed airway smooth muscle differentiation was driven by the autocrine release of TGF-β1 in response to activation by mast cell β-tryptase. Importantly, in vivo we found that in bronchial mucosal biopsies from asthmatics the intensity of -smooth muscle actin expression was strongly related to the number of mast cells within or adjacent to an airway smooth muscle bundle. These findings suggest that mast cell localization in the airway smooth muscle bundle promotes airway smooth muscle cell differentiation into a more contractile phenotype, thus contributing to the disordered airway physiology that characterizes asthma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Funding was received from Asthma UK, DoH Clinician Scientist Award (to C.B.) and Wellcome Senior Clinical Fellowship (to C.B.).

² Address correspondence and reprint requests to Dr. Christopher E. Brightling, Institute for Lung Health, Department of Infection, Inflammation, and Immunity, University of Leicester, Glenfield Hospital, LE3 9QP, Leicester, U.K. E-mail: ceb17{at}le.ac.uk

³ Abbreviations used in this paper: AHR, airway hyper-responsiveness; ASM, airway smooth muscle; -SMA, -smooth muscle actin; COPD, chronic obstructive pulmonary disease; GMFI, geometric mean fluorescent intensity; HLMC, human lung mast cell; HMC-1, human mastocytoma cell line.

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