Role of сathepsin G in pathogenesis of chronic obstructive lung disease: possible ways of regulation

Abstract

This review article presents the literature data supporting an idea on the role of serine proteases, and, especially, cathepsin G (CG), in pathogenesis of chronic obstructive pulmonary disease (COPD). Most studies show that the imbalance in protease-antiprotease systems in COPD is one of the main factors in the disease progression and deterioration of patient’s prognosis. CG seems to act simultaneously in several main pathogenetic aspects of the disease: it stimulates inflammation in the bronchial mucous membranes, leads to remodeling of elastic framework of the lungs, causes degradation of the phospholipid transfer protein (PLTP). A study by Gudmann et al. (2018) reported on quantitative assays of elastin fragments, which are formed under the action of CG (EL-CG) and significantly increased in COPD, thus proving the effects of CG on destruction of elastic framework in lungs. In a recent study, Rønnow S.R. et al. have recommended the assays of EL-CG fragments, reflecting elastin CG remodeling, for use as a prognostic biomarker for overall mortality in COPD. The effect of CG on PLTP was studied in the works of Brehm A. et al. It is known that the anti-inflammatory effect of PLTP is mediated by macrophages, via the ATP-binding cassette transporter (ABCA1), blocking the nuclear factor light chain enhancer (NF-kB) and reducing secretion of pro-inflammatory mediators by these cells, including (TNFα). The CG inhibition in bronchoalveolar lavage fluid (BALF) of the patients with COPD consistently disrupts its ability to cleave recombinant PLTP (rPLTP). At the same time, the highest CG activity was registered in BALF from smokers and in patients with COPD. Negative correlations between CG activity and PLTP level were detected. With respect to above, one may expect an increased interest for developing the inhibitors of serine proteases, including CG. E.g., the sunflower trypsin-1 inhibitor (SFTI-1) is a potent CG inhibitor, showing a significant increase of its activity when the P1 residue is replaced from Arg5 to Phe5. According to most researchers, powerful and selective CG inhibitors may be developed in future on the basis of SFTI-1, thus requiring further in-depth research.