title: MAG-EPA and 17,18-EpETE target cytoplasmic signalling pathways to reduce short-term airway hyperresponsiveness.
abstract: This study was aimed to investigate the role of eicosapentaenoic acid monoacylglyceride (MAG-EPA) and 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) on the regulation of contractile reactivity and nuclear protein expression in 72-h-cultured and TNF-α-treated guinea pig tracheal rings. Tension measurements performed on native tissues demonstrated that the cytochrome P-450 epoxygenase (CYP450)-dependent EPA metabolite, 17,18-EpETE, displayed a higher potency than MAG-EPA in inhibiting U-46619-induced tone. Calphostin C (a PKC inhibitor), whether in association or not with MAG-EPA or 17,18-EpETE, had no further effect, while 17,18-EpETE and Y-27632 (a Rho kinase inhibitor) yielded additive effects. Of note, MAG-EPA and 17,18-EpETE pre-treatments normalized the contractile responses to broncho-constrictive agents in 72-h-cultured trachea. The enhanced expression of TNF-α, P-p65-nuclear factor kappaB (NF)-κB, c-fos and c-Jun in 72-h-cultured tissues likely contributed to the hyperresponsiveness. β-Escin-permeabilized preparations demonstrated that 17,18-EpETE abolished Ca(2+) hypersensitivity, suggesting a blunting of PKC and/or Rho kinase activation. Lastly, activation of NF-κB and activating protein-1 (AP-1) signalling by exogenous TNF-α markedly increased the contractile response to MCh, through an increase in 17-kDa PKC-potentiated inhibitory protein of PP1 (CPI-17) phosphorylation and IκBα degradation. Dual incubation of 17,18-EpETE with calphostin C or Y-27632 induced cumulative inhibitory effects on MCh responses in TNF-α-incubated tracheal rings. 17,18-EpETE also reduced the detection level of P-p65-NF-κB and AP-1 subunits. The present data provide evidence that MAG-EPA, through its bioactive metabolite, represents a prospective pharmacological target in respiratory diseases.
authors.affiliation: Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.
authors.forename: Rayan
authors.initials: R
authors.lastname: Khaddaj-Mallat
authors.affiliation: Le Bilarium, Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada. Eric.Rousseau@USherbrooke.ca.
authors.forename: Éric
authors.initials: É
authors.lastname: Rousseau
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D016084:Bronchoconstriction; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D050178:Monoglycerides / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D015398:Signal Transduction; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: C588285:1-eicosapentaenoylglycerol; D001095:Arachidonic Acids; D016085:Bronchoconstrictor Agents; D050178:Monoglycerides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C070378:17,18-epoxy-5,8,11,14-eicosatetraenoic acid; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D002118:Calcium
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