Abstract
Abstract Inflammation, oxidative stress, and protease-antiprotease imbalance have been suggested as a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, little is known about how they interact. The objectives of this study were to elucidate the effect of cigarette smoke extract (CSE) on the neutrophil elastase (NE)-induced inflammatory response and its molecular mechanism in bronchial epithelial cells. NE activated extracellular signal-regulated kinase (ERK) and induced IL-8 production. Blocking ERK activation by MEK inhibitor (U0126) suppressed NE-induced IL-8 secretion and pre-incubation with proteinase-activated receptor 2 blocking peptide (PAR2BP) inhibited both NE-induced ERK activation and subsequent IL-8 release, suggesting that NE-induced IL-8 production is dependent on PAR2-mediated ERK activation. Interestingly, pre-exposure with CSE markedly enhanced NE-induced IL-8 production. Knock-down of PAR2 expression by transfection with siRNAs blocked the synergistic effect of CSE on NE-induced IL-8 production. Therefore, we next investigated the effect of CSE on PAR2 expression. CSE, but not NE, increased the expression of PAR2 mRNA and surface membrane protein. Inhibition of p38 MAP kinase reduced PAR2 expression by CSE, while inhibition of ERK and Akt pathway was without effect. Moreover, p38 inhibition completely abrogated CSE-induced enhancement of IL-8 production in NE-treated cells. Taken together, these results suggest that CSE up-regulates PAR2 in normal human bronchial epithelial cells, thereby enhancing the inflammatory response to NE.
Published Version
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