Background: Proteolytic events are involved in the progression of lung fibrosis. Results: Cathepsin B participates in lung fibroblast differentiation by triggering TGF-␤1/Smad pathway. TGF-␤1 up-regulates secretion of cystatin C. Conclusion: TGF-␤1 promotes cystatin C-dependent inhibition of extracellular matrix-degrading cathepsins. Significance: Both cathepsin B and cystatin C could play a crucial role in fibrosis by favoring accumulation of ECM.

Human cysteine cathepsins (family C1, clan CA) have long been regarded as ubiquitous household enzymes, primarily involved in the recycling and degradation of proteins in lysosomes. This opinion has changed considerably during recent decades, however, with the demonstration of their involvement in various physiological processes. A growing body of evidence supports the theory that cathepsins play specific functions in lung homeostasis and pathophysiological events such as asthma, lung fibrosis (including idiopathic pulmonary fibrosis), chronic obstructive pulmonary disease (embracing emphysema and chronic bronchitis), silicosis, bronchopulmonary dysplasia or tumor invasion. The objective of this review is to provide an update on the current knowledge of the role of these enzymes in the lung. Particular attention has been paid to the understanding of the role of these proteases and their natural inhibitors, cystatins (family I25, clan IH), in TGF-β1-driven fibrotic processes with an emphasis on lung fibrosis.

Pulmonary fibrosis is a progressive disease characterized by a widespread accumulation of myofibroblasts and extracellular matrix components. Growing evidences support that cysteine cathepsins, embracing cathepsin B (CatB) that affects TGF-β1-driven Smad pathway, along with their extracellular inhibitor cystatin C, participate in myofibrogenesis. Here we established that curcumin, a potent antifibrotic drug used in traditional Asian medicine, impaired the expression of both α-smooth muscle actin and mature TGF-β1 and inhibited the differentiation of human lung fibroblasts (CCD-19Lu cells). Curcumin induced a compelling upregulation of CatB and CatL. Conversely cystatin C was downregulated, which allowed the recovery of the peptidase activity of secreted cathepsins and the restoration of the proteolytic balance. Consistently, the amount of both insoluble and soluble type I collagen decreased, reaching levels similar to those observed for undifferentiated fibroblasts. The signaling pathways activated by curcumin were further examined. Curcumin triggered the expression of nuclear peroxisome proliferator-activated receptor γ (PPARγ). Contrariwise PPARγ inhibition, either by an antagonist (2-chloro-5-nitro-N-4-pyridinyl-benzamide) or by RNA silencing, restored TGF-β1-driven differentiation of curcumin-treated CCD-19Lu cells. PPARγ response element (PPRE)-like sequences were identified in the promoter regions of both CatB and CatL. Finally, we established that the transcriptional induction of CatB and CatL depends on the binding of PPARγ to PPRE sequences as a PPARγ/Retinoid X Receptor-α heterodimer.

An excessive deposition of extracellular matrix proteins is the hallmark of fibrotic disorders. Cats are potent collagenases and might be essential for lung homeostasis. Taken together, increase of cystatin C in IPF BALFs may reflect abnormal regulation of proteolytic activity of Cats in lung, which in turn can promote the development of fibrosis.

There is now growing evidence that lung cysteine cathepsins take part in several biological processes and pulmonary homeostasis, although their exact functions remain to be clarified. Their production is increased in most tumors and in chronic and acute inflammatory lung disorders such as silicosis, COPD (emphysema, chronic bronchitis), asthma, and bronchopulmonary dysplasia. Cathepsins aggravate the extent and severity of inflammation and contribute to the remodeling and/or degradation of the extracellular matrix and the basement membrane. Cysteine cathepsins and their inhibitors (stefins and cystatins) are both potential markers of the prognosis and diagnosis of cancer. Cathepsin S is a potential marker of asthma, while cathepsin K may be a useful immunohistological marker of lymphangioleiomyomatosis and of granulomas in interstitial lung diseases. This review covers selected aspects of our current knowledge about lung cysteine cathepsins and outlines some recent advances. We also examine the implications of using cathepsin inhibitors to treat a variety of bone and joint diseases like rheumatoid arthritis, osteoporosis, and bone metastasis for the risk of deleterious side effects on the lungs.

The activity of cysteine cathepsin B increased markedly in lung homogenates and in bronchoalveolar lavage fluids (BALF) of the mouse model of bleomycin-induced lung fibrosis after 14 days of challenge. In contrast the level of the cysteine cathepsin inhibitor cystatin C was unaffected in BALF of wild-type and cathepsin B-deficient mice. Therefore, murine cystatin C is not a reliable marker of fibrosis during bleomycin-induced lung fibrosis. Current data are in sharp contrast to previous analysis carried on human BALF from patients with idiopathic pulmonary fibrosis, for which the level of cathepsin B remained unchanged while cystatin C was significantly increased.

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