Cysteine Cathepsins: Markers and Therapy Targets in Lung Disorders

Abstract

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.

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

“…As shown in an earlier report, exposure of cardiac fibroblasts to exogenous cystatin C resulted in the inhibition of Cat B and accumulation of fibronectin and collagens (64). Conversely, during lung inflammations associated with widespread ECM breakdown, the BALFs cathepsin/ cystatin ratio was reversed in favor of uncontrolled proteolysis (8,22).…”

“…Conversely to that observed for CCD-19Lu myofibroblasts, we detected Cat activity in IPF culture media. This residual proteolytic activity of IPF samples obtained from lung biopsies probably relied on the presence (in addition to fibroblastic cells) of some resident macrophages and epithelial cells that are the primary source of extracellular Cats (8,22,58,59). Nevertheless, as observed for the CCD-19Lu model, inhibition of cystatin C by siRNA drastically rescued (4 -5-fold) Cat B activity (p Ͻ 0.001) (Fig.…”

“…Among various classes of proteases, there is now a growing body of evidence that cysteine cathepsins (Cats) participate in pulmonary homeostasis (8). Although their exact functions remain to be clarified, Cats are potent ECM-degrading enzymes (9,10).…”

Human cystatin C: A new biomarker of idiopathic pulmonary fibrosis?

“…There is now a growing body of evidence that cysteine Cats take part in pulmonary homeostasis [14]. Dysregulation of the protease/antiprotease balance in favor to a reduction of the proteolytic activity by endogenous inhibitors may promote progression of the lung fibrosis.…”

“…Cystatin C is a highly potent inhibitor of cysteine cathepsins (Cat) (family C1; MEROPS: the peptidase database: [9]) and is considered to be the major extracellular cysteine protease inhibitor [11,12]. The lung expression of cysteine Cats and their putative functions have been reviewed elsewhere [13,14]. Cystatin C that is expressed by a broad variety of human cells and tissues, has a widespread distribution, and is ubiquitously found in body fluids at significant concentrations, especially in milk, seminal plasma, and cerebrospinal fluid [11].…”