TMPRSS4: a novel serine protease involved in IPF development?

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive and lethal lung disease characterized by the expansion of the fibroblast population and excessive extracellular matrix accumulation with the subsequent destruction of the lung architecture. Its pathogenesis is incompletely understood but evidence suggests an epithelial pathway in which IPF may result from epithelial microinjuries and activation and abnormal wound healing. TMPRSS4 is a novel type II transmembrane serine protease found at the cell surface. Although their biological functions are unknown it has been suggested that TMPRSS4 promotes migration and facilitates the epithelial to mesenchymal transition (EMT), two critical processes in the pathogenesis of IPF. Thus, we hypothesized that overexpression of TMPRSS4 in the lung could promote the initiation and/or progression of IPF.AimTo determine the role of TMPRSS4 in IPF.MethodsWe first examined the lung expression and localization of TMPRSS4 in IPF and normal lungs by qPCR and immunohistochemistry. Additionally, we measured the expression of TMPRSS4 in human lung fibroblasts and one alveolar and one bronchial epithelial cell lines. Then we explored the role of this protease in an experimental model of lung fibrosis. TMPRSS4 haplodeficient and wild type mice received an intratracheal instillation of bleomycin and were studied at 28 days post‐instillation.ResultsWe found that this protease is not expressed in normal human lungs while variable amounts of the mRNA were found in IPF lungs (2−DCT 1.1×10−2 ± 9.4×10−5). TMPRSS4 was primarily expressed by epithelial and mast cells. The protease was not found in lung fibroblasts but different levels of mRNA were revealed in alveolar (2−DCT 7.5×10−7 ± 2×10−7) and bronchial (2−DCT 4.2×10−5 ± 3.6×10−6) epithelial cells. The lung fibrotic response, measured by hydroxyproline ( 178.9 ± 12.4 versus 110.7 ± 13.8 mg/lung; p<0.05) and morphology (40% versus 15% extent of the lesions) was significantly attenuated in the haplodeficient mice.ConclusionsOur findings indicate that TMPRSS4 may have a profibrotic role in IPF and other fibrotic lung disorders.Support or Funding InformationPosgrado en Ciencias Biológicas, UNAM; CONACYT SALUD‐2014‐01‐234088