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Am J Physiol Lung Cell Mol Physiol 278: L193-L201, 2000;
1040-0605/00 $5.00
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Vol. 278, Issue 1, L193-L201, January 2000

Mast cell tryptase stimulates human lung fibroblast proliferation via protease-activated receptor-2

Ian A. Akers1, Maddy Parsons1, Michael R. Hill1, Morley D. Hollenberg2, Shahin Sanjar3, Geoffrey J. Laurent1, and Robin J. McAnulty1

1 Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, The Royal Free and University College Medical School, The Rayne Institute, London WC1E 6JJ; 3 Respiratory Diseases Unit, Glaxo Wellcome Research and Development Limited, Medicines Research Centre, Stevenage SG1 2NY, United Kingdom; and 2 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1

Mast cells play a potentially important role in fibroproliferative diseases, releasing mediators including tryptase that are capable of stimulating fibroblast proliferation and procollagen synthesis. The mechanism by which tryptase stimulates fibroblast proliferation is unclear, although recent studies suggest it can activate protease-activated receptor (PAR)-2. We therefore investigated the role of PAR-2 in tryptase-induced proliferation of human fetal lung and adult lung parenchymal and airway fibroblasts and, for comparative purposes, adult dermal fibroblasts. Tryptase (0.7-70 mU/ml) induced concentration-dependent increases in proliferation of all fibroblasts studied. Antipain, bis(5-amidino-2-benzimidazolyl)methane, and benzamidine inhibited tryptase-induced fibroblast proliferation, demonstrating that proteolytic activity is required for the proliferative effects of tryptase. RT-PCR demonstrated the presence of PAR-2 mRNA, and immunohistochemical staining localized PAR-2 to the cell surface of lung fibroblasts. In addition, specific PAR-2 activating peptides, SLIGKV and SLIGRL, mimicked the proliferative effects of tryptase. In contrast, human dermal fibroblasts only weakly stained with the PAR-2 antibody, PAR-2 mRNA was almost undetectable, and fibroblasts did not respond to PAR-2 activating peptides. These results suggest that tryptase induces lung, but not dermal, fibroblast proliferation via activation of PAR-2 and are consistent with the hypothesis that the release of tryptase from activated mast cells may play an important role in the fibroproliferative response observed in asthma, chronic obstructive pulmonary disease, and patients with pulmonary fibrosis.

asthma; airway remodeling; interstitial fibrosis; serine proteinase


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