Abstract
Although inflammation, oxidative stress, and protease-antiprotease imbalance have been referred to as a pathogenic triad in chronic obstructive pulmonary disease (COPD), 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. We observed that NE activated extracellular signal-regulated kinase (ERK) and induced IL-8 production. Blocking ERK activation using a MEK inhibitor (U0126) suppressed NE-induced IL-8 secretion and knockdown of proteinase-activated receptor 2 (PAR2) using siRNAs 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 to CSE markedly enhanced NE-induced IL-8 production. As PAR2 acts as a receptor for NE, we next investigated the effect of CSE on PAR2 expression as a molecular mechanism for the increased IL-8 production induced by NE in CSE exposed cells. CSE, but not NE, increased the expression of PAR2 mRNA and surface membrane protein. Inhibition of p38 MAPK reduced PAR2 expression induced by CSE while inhibition of the ERK and Akt pathway had no effect. Consequently, p38 inhibition significantly abrogated CSE-induced enhancement of IL-8 production in NE-treated cells. Of note, we observed increased PAR2 levels in lung homogenates and lung epithelial cells from CSE-treated mice and from both smokers and patients with COPD. Taken together, these results suggest that CSE upregulates PAR2 in normal human bronchial epithelial cells, thereby enhancing the inflammatory response to NE.
Highlights
Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by the presence of airflow limitation resulting from airway inflammation, airway remodeling, and parenchymal destruction
These results suggest that neutrophil elastase (NE)-induced IL-8 production is enhanced by cigarette smoke extract (CSE) pretreatment via proteinase-activated receptor 2 (PAR2)
COPD is an inflammatory disorder and neutrophils are considered to play an integral role in the pathophysiology of COPD13,14
Summary
Chronic obstructive pulmonary disease (COPD) is a progressive disease characterized by the presence of airflow limitation resulting from airway inflammation, airway remodeling, and parenchymal destruction. Previous studies have shown different regulations of PAR expression according to inflammatory mediators and cell types. The distribution of PAR2 and its response to inflammatory mediators have been studied, its function in bronchial epithelial cells and its response to cigarette smoke extract (CSE) are unclear. Both inflammation and protease-antiprotease imbalance interact with each other in the pathogenesis of COPD, and the inhibition of its pathways are an appealing approach for therapeutic interventions to break the vicious cycle. The objective of this study was to elucidate the effect of CSE on the NE-induced inflammatory response and its molecular mechanism in bronchial epithelial cells
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