title: Pro-Resolving Effects of Resolvin D2 in LTD4 and TNF-α Pre-Treated Human Bronchi.
abstract: 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 RvD2, a member of the D-series resolving family, with concomitant effects on ASM mechanical reactivity. The role and mode of action of RvD2 were assessed in an in vitro model of human bronchi under pro-inflammatory conditions, induced either by 1 μM LTD4 or 10 ng/ml TNF-α pre-treatment for 48h. TNF-α 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-α pre-treated human bronchi when compared to control (untreated) human bronchi. In contrast, RvD2 treatments reversed 5-LOX/β-actin and CysLTR1/β-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 RvD2 on LTD4 or TNF-α induced hyper-responsiveness. Combined treatment with 300 nM RvD2 and 1 μM WRW4 (an ALX/FPR2 receptor inhibitor) blunted the pro-resolving and broncho-modulatory effects of RvD2. The present data provide new evidence regarding the role of RvD2 in a human model of airway inflammation and hyperrresponsiveness.
authors.affiliation: Department of Obstetrics-Gynecology Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Rayan
authors.initials: R
authors.lastname: Khaddaj-Mallat
authors.affiliation: Service of Thoracic Surgery, CHUS Felurimont, Sherbrooke, Quebec, Canada.
authors.forename: Chantal
authors.initials: C
authors.lastname: Sirois
authors.affiliation: Service of Thoracic Surgery, CHUS Felurimont, Sherbrooke, Quebec, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Sirois
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Edmond
authors.initials: E
authors.lastname: Rizcallah
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Sofia
authors.initials: S
authors.lastname: Marouan
authors.affiliation: Nursery School, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Morin
authors.affiliation: Department of Obstetrics-Gynecology Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Éric
authors.initials: É
authors.lastname: Rousseau
mesh_terms: D000199:Actins / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016084:Bronchoconstriction / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control; D017998:Leukotriene D4 / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D018077:Receptors, Leukotriene / Q000378:metabolism; D046509:Tissue Culture Techniques; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D018077:Receptors, Leukotriene; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C545423:resolvin D2; D004281:Docosahexaenoic Acids; D017998:Leukotriene D4; D001094:Arachidonate 5-Lipoxygenase; C583212:ALOX5 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C083169:leukotriene D4 receptor