Cigarette smoke induces overexpression of active human cathepsin S in lungs from current smokers with or without COPD

Abstract

Cigarette smoking has marked effects on lung tissue, including induction of oxidative stress, inflammatory cell recruitment, and a protease/antiprotease imbalance. These effects contribute to tissue remodeling and destruction resulting in loss of lung function in chronic obstructive pulmonary disease (COPD) patients. Cathepsin S (CatS) is a cysteine protease that is involved in the remodeling/degradation of connective tissue and basement membrane. Aberrant expression or activity of CatS has been implicated in a variety of diseases, including arthritis, cancer, cardiovascular, and lung diseases. However, little is known about the effect of cigarette smoking on both CatS expression and activity, as well as its role in smoking-related lung diseases. Here, we evaluated the expression and activity of human CatS in lung tissues from never-smokers and smokers with or without COPD. Despite the presence of an oxidizing environment, CatS expression and activity were significantly higher in current smokers (both non-COPD and COPD) compared with never-smokers, and correlated positively with smoking history. Moreover, we found that the exposure of primary human bronchial epithelial cells to cigarette smoke extract triggered the activation of P2X7 receptors, which in turns drives CatS upregulation. The present data suggest that excessive CatS expression and activity contribute, beside other proteases, to the deleterious effects of cigarette smoke on pulmonary homeostasis.

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

“…Proteases are well known to play an important role in the pathogenesis of COPD [1,9]. Elevated CTSS is observed in lung tissue, bronchoalveolar lavage fluid (BALF) and plasma of COPD patients as well as current smokers with or without COPD [57][58][59]. Importantly, elevated CTSS activity is observed in COPD [57] and appears to increase with disease severity [58].…”

Regulation of the Proteolytic Activity of Cysteine Cathepsins by Oxidants

“…Also, analysis by redox sensing probes of the inactivation of CatS by H 2 O 2 supported the formation of Cys25 sulfenic acid followed by a slower conversion to sulfinic acid [77]. This protective mechanism may explain the maintenance of cysteine cathepsin activity during emphysema [76] and inflammatory phenomena such as silicosis [43]. By broadening the proposal of Rauhala and coworkers [111], one could hypothesize that reversible inhibition of cathepsins by hydrogen peroxide may represent a complementary mechanism of protection against more harmful oxidants (i.e., hydroxyl radical, hypochlorous acid, or peroxynitrate).…”

“…Comparably, cathepsins B, K, L and S were capable of processing thyroglobulin under conditions mimicking the extracellular oxidizing environment of the thyroid follicle lumen (redox potential of −150 mV and neutral pH 7.2) [100]. Also, despite a significantly higher oxidative stress index (OSI) in current smokers compared to nonsmokers, an increase of CatS activity was found in lung tissue of smokers [76]. Addition of N-acetyl cysteine or GSH led to a partial recovery of CatS activity following incubation with CSE, H2O, and ONOO − [77].…”

“…Recently, we demonstrated that CatS expression, as well its enzymatic activity, is more elevated in current smokers (both non-COPD and COPD patients) compared to never-smokers, and these correlate positively with smoking history [76]. Exposure of primary human bronchial epithelial cells to cigarette smoke extract (CSE) triggers the activation of purinergic P2X7 receptors, which in turn drive CatS upregulation [76]. Despite a marked increase of oxidants associated with cigarette smoke and a subsequent oxidant/antioxidant imbalance, overall data suggest that CatS may contribute, in conjunction with other proteases, to elastinolysis and subsequent parenchymal destruction in emphysema [77].…”

“…Also, cigarette smoke enhances the production of IL-18 (an IFN-γ inducing factor), and induces CatS expression in lung macrophages of cigarette smoke-exposed mice [75]. Recently, we demonstrated that CatS expression, as well its enzymatic activity, is more elevated in current smokers (both non-COPD and COPD patients) compared to never-smokers, and these correlate positively with smoking history [76]. Exposure of primary human bronchial epithelial cells to cigarette smoke extract (CSE) triggers the activation of purinergic P2X7 receptors, which in turn drive CatS upregulation [76].…”