Membrane-anchored Serine Protease Matriptase Is a Trigger of Pulmonary Fibrogenesis

Abstract

Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease that remains refractory to current therapies.Objectives: To characterize the expression and activity of the membrane-anchored serine protease matriptase in IPF in humans and unravel its potential role in human and experimental pulmonary fibrogenesis.Methods: Matriptase expression was assessed in tissue specimens from patients with IPF versus control subjects using quantitative reverse transcriptase-polymerase chain reaction, immunohistochemistry, and Western blotting, while matriptase activity was monitored by fluorogenic substrate cleavage. Matriptaseinduced fibroproliferative responses and the receptor involved were characterized in human primary pulmonary fibroblasts by Western blot, viability, and migration assays. In the murine model of bleomycin-induced pulmonary fibrosis, the consequences of matriptase depletion, either by using the pharmacological inhibitor camostat mesilate (CM), or by genetic down-regulation using matriptase hypomorphic mice, were characterized by quantification of secreted collagen and immunostainings.Measurements and Main Results: Matriptase expression and activity were up-regulated in IPF and bleomycin-induced pulmonary fibrosis. In cultured human pulmonary fibroblasts, matriptase expression was significantly induced by transforming growth factor-b. Furthermore, matriptase elicited signaling via protease-activated receptor-2 (PAR-2), and promoted fibroblast activation, proliferation, and migration. In the experimental bleomycin model, matriptase depletion, by the pharmacological inhibitor CM or by genetic downregulation, diminished lung injury, collagen production, and transforming growth factor-b expression and signaling.Conclusions: These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by CM, which is already in clinical use for other diseases, may represent potential therapies for IPF.

Proteases: Pivot Points in Functional Proteomics

“…Matriptases 1 and 2, and prostasin are expressed in human epithelium, and inhibited by their cognate Kunitz-type inhibitors, membrane-anchored hepatocyte growth factor activator inhibitors (HAI) 1 and 2 [79]. Matriptase overexpression elicits signaling via the PAR-2, and promotes fibroblast activation, proliferation, and migration in idiopathic pulmonary fibrosis [80]. Matriptase proteolytically activates hepatocyte growth factor (HGF) that binds to its receptor c-Met, a receptor tyrosine kinase.…”

Human airway trypsin‐like protease exerts potent, antifibrotic action in pulmonary fibrosis

“…Mice were killed at the indicated time points after bleomycin challenge. To obtain mouse BAL, a standard approach was performed, as previously described (5). After BAL centrifugation, cell number was determined in the remaining pellets, and the supernatants were stored at 280°C until further analysis.…”

“…Although the molecular mechanisms involved in the development of IPF are incompletely understood, recent studies have identified potential targets for therapeutic interventions (4). Among them, serine proteases have been demonstrated to critically contribute to the pathogenesis of fibrotic lung disorders (5)(6)(7)(8), although the exact mechanisms are not fully understood.…”

Traditional Chinese medicine for pulmonary fibrosis therapy: Progress and future prospects

“…Pulmonary fibrosis (PF) is a serious lung disorder characterized by excessive accumulation of extracellular matrix (ECM) (Wollin et al, 2015;Bardou et al, 2016). In the early period of PF, the affected lungs are mainly inflammatory cell infiltration, edema and congestion, and then converted to the injury of alveolar epithelial cells (AEC), abnormal proliferation of ECM-producing cells (mesenchymal cells including fibroblasts (FB) and myofibroblasts (MFb)), the overproduction of ECM (collagens, laminin, tenascin-C, etc.…”