LSC Abstract – Human airway trypsin-like protease: Friend or foe in idiopathic pulmonary fibrosis?

Abstract

Introduction: Human Airway Trypsin-like protease (HAT) belongs to the membrane-anchored serine proteases family and is expressed in the lung. While its pathophysiological functions remain unknown, HAT is involved in pulmonary remodeling processes such as asthma. In bronchial airways HAT stimulates fibroblast proliferation through Protease-Activated Receptor-2, which is instrumental in IPF. So far, the role of HAT in IPF has never been investigated. Methods: In controls or patients with IPF, HAT expression was analyzed in lung biopsies by immunohistochemistry, and by Western-blot (WB) in lung homogenates, Broncho-Alveolar Lavages (BAL) and primary pulmonary fibroblasts. In lung homogenates and BAL, HAT activity was measured, by the cleavage of a specific chromogenic substrate. In vitro, the effects of HAT on fibrotic markers expression, migration and proliferation were assessed in human primary pulmonary fibroblasts using WB, WST-1 and Boyden chamber assays. Results: HAT is increased in IPF lungs in epithelial cells, (myo)fibroblasts and macrophages. Accordingly, HAT expression and activity are enhanced in lung and BAL from IPF patients. In fibroblasts, HAT induces phosphorylation of kinases such as ERK, decreases fibronectine and collagen expression, strongly impairs migration. Moreover, HAT does not increase pulmonary fibroblasts proliferation. Conclusions: Unlike its deleterious role in chronic inflammatory disease, in IPF, HAT induces anti-fibrotic responses in vitro. Its deregulated expression in patients with IPF may constitute an insufficient mechanism of protection. Although further studies are warranted in HAT-deficient mice, our results suggest that an induction of HAT in IPF could be beneficial.