Pulmonary fibrosis (PF) is a chronic disease characterized by fibrous thickening in the interstitial spaces of the lung. Specifically, idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible PF of unknown etiology (median survival: 2–4 years). During PF early phase, alterations in alveolar epithelial cells induce the proliferation and differentiation of fibroblasts into myofibroblasts. Extracellular matrix (ECM) overproduction by myofibroblasts induces a dysregulation of ECM remodeling in fibrotic foci, which is closely associated with an altered protease/antiprotease balance. Among proteases involved, some cysteine cathepsins (a family consisting of 11 members in humans) are potent collagenases and elastases which participate in ECM remodeling [1 Mol Aspects Med 2022 ;  88 : 101086

Cliquez ici pour aller à la section Références]. During PF, the cathepsin/cystatin (i.e., endogenous cathepsin inhibitors) balance is impaired in favor of cystatins.

Characterization of cystatin C (CysC), a broad-spectrum circulating cathepsin inhibitor, was conducted by immunochemical analysis of control (n=11) and IPF (n=25) bronchoalveolar lavage fluid. Supernatants of primary human fibroblasts (IPF patients) were collected for measuring peptidase activities of extracellular cysteine cathepsins. CCD-19Lu human lung fibroblasts were used as a model of TGF-β1-dependent myodifferentiation to study the regulation of CysC and cystatin M/E (CysM/E) during pulmonary fibrosis.

CysC is overexpressed in bronchoalveolar lavage fluids from IPF patients and is oversecreted during myodifferentiation, promoting collagen I deposition. Accordingly, we proposed CysC as a candidate IPF biomarker. Alternatively, cystatin M/E (CysM/E) [2 Cancers 2021 ;  13 : 1877

Cliquez ici pour aller à la section Références], another potent cysteine cathepsin inhibitor, is both overexpressed and oversecreted during differentiation of lung fibroblasts.

CysC and CysM/E are key molecular players involved in the TGF-β1-dependent myofibrogenesis. Secreted forms impair both collagenolytic and elastinolytic activities of extracellular cysteine cathepsins and subsequently may promote PF development.