Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by epithelial cell activation, expansion of the fibroblast population and excessive extracellular matrix accumulation. The mechanisms are incompletely understood but evidence indicates that the deregulation of several proteases contributes to its pathogenesis. Transmembrane protease serine 4 (TMPRSS4) is a novel type II transmembrane serine protease that may promote migration and facilitate epithelial to mesenchymal transition (EMT), two critical processes in the pathogenesis of IPF. Thus, we hypothesized that over-expression of TMPRSS4 in the lung could promote the initiation and/or progression of IPF. In this study we first evaluated the expression and localization of TMPRSS4 in IPF lungs by real time PCR, western blot and immunohistochemistry. Then we examined the lung fibrotic response in wild-type and TMPRSS4 deficient mice using the bleomycin-induced lung injury model. We found that this protease is upregulated in IPF lungs, where was primarily expressed by epithelial and mast cells. Paralleling the findings in vivo, TMPRSS4 was expressed by alveolar and bronchial epithelial cells in vitro and unexpectedly, provoked an increase of E-cadherin. No expression was observed in normal human or IPF lung fibroblasts. The lung fibrotic response evaluated at 28 days after bleomycin injury was markedly attenuated in the haplodeficient and deficient TMPRSS4 mice. By morphology, a significant reduction of the fibrotic index was observed in KO and heterozygous mice which was confirmed by measurement of collagen content (hydroxyproline: WT: 164±21.1 μg/lung versus TMPRSS4 haploinsufficient: 110.2±14.3 μg/lung and TMPRSS4 deficient mice: 114.1±24.2 μg/lung (p<0.01). As in IPF, TMPRSS4 was also expressed in epithelial and mast cells. These findings indicate that TMPRSS4 is upregulated in IPF lungs and that may have a profibrotic role.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most aggressive of the interstitial lung diseases (ILD), leading to respiratory failure and premature death with a median life expectancy of about three years from diagnosis [1, 2]
Our results demonstrated that TMPRSS4 is upregulated in epithelial and mast cells in IPF lungs and that the fibrotic response to bleomycin is attenuated in TMPRSS4-deficient mice suggesting a profibrotic role for this protease
hypersensitivity pneumonitis (HP) samples were used because it represents an inflammatory-driven ILD that often evolve to fibrosis
Summary
Idiopathic pulmonary fibrosis (IPF) is the most aggressive of the interstitial lung diseases (ILD), leading to respiratory failure and premature death with a median life expectancy of about three years from diagnosis [1, 2]. IPF is characterized by the abnormal activation of alveolar epithelial cells, which produce a variety of mediators causing migration, proliferation and differentiation of fibroblasts into myofibroblasts which in turn secrete large amounts of extracellular matrix resulting in abnormal remodeling of the lung architecture [1, 3, 4]. The biopathological processes leading to IPF and the mechanisms responsible for the abnormal activation of epithelial cells and fibroblasts have not been elucidated. Proteases play crucial roles in a large variety of physiologic and pathological processes including the degradation of basement membrane and extracellular matrix (ECM) and tissue remodeling [5, 6], and several matrix metalloproteases have been found deregulated in IPF [7]. More than 2% of the genes code for a complex system of more than 700 proteases and inhibitors of proteases [8]
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