Pro-Resolving Effects of Resolvin D2 in LTD4 and TNF-α Pre-Treated Human Bronchi

Inflammation is a major burden in respiratory diseases, resulting in airway hyperresponsiveness. Our hypothesis is that resolution of inflammation may represent a long-term solution in preventing human bronchial dysfunctions. The aim of the present study was to assess the anti-inflammatory effects of RvD(2), a member of the D-series resolving family, with concomitant effects on ASM mechanical reactivity. The role and mode of action of RvD(2) were assessed in an in vitro model of human bronchi under pro-inflammatory conditions, induced either by 1 mu M LTD4 or 10 ng/ml TNF-alpha pre-treatment for 48h. TNF-alpha and LTD4 both induced hyperreactivity in response to pharmacological stimuli. Enhanced 5-Lipoxygenase (5-LOX) and cysteinyl leukotriene receptor 1 (CysLTR1) detection was documented in LTD4 or TNF-alpha pre-treated human bronchi when compared to control (untreated) human bronchi. In contrast, RvD(2) treatments reversed 5-LOX/beta-actin and CysLTR1/beta-actin ratios and decreased the phosphorylation levels of AP-1 subunits (c-Fos, c-Jun) and p38-MAP kinase, while increasing the detection of the ALX/FPR2 receptor. Moreover, various pharmacological agents revealed the blunting effects of RvD(2) on LTD4 or TNF-alpha induced hyper-responsiveness. Combined treatment with 300 nM RvD(2) and 1 mu M WRW4 (an ALX/FPR2 receptor inhibitor) blunted the pro-resolving and broncho-modulatory effects of RvD(2). The present data provide new evidence regarding the role of RvD(2) in a human model of airway inflammation and hyperrresponsiveness.