Reversal of IL-13-induced inflammation and Ca2+ sensitivity by resolvin and MAG-DHA in association with ASA in human bronchi

Abstract

The aim of this study was to investigate the effects of resolvin D1 (RvD1), as well as the combined treatment of docosahexaenoic acid monoglyceride (MAG-DHA) and acetylsalicylic acid (ASA), on the resolution of inflammation markers and Ca2+ sensitivity in IL-13-pretreated human bronchi (HB). Tension measurements performed with 300nM RvD1 largely abolished (50%) the over-reactivity triggered by 10ng/ml IL-13 pretreatment and reversed hyper Ca2+ sensitivity. Addition of 300nM 17(S)-HpDoHE, the metabolic intermediate between DHA and RvD1, displayed similar effects. In the presence of 100μM ASA (a COX inhibitor), the inhibitory effect of 1μM MAG-DHA on muscarinic tone was further amplified, but not in the presence of Ibuprofen. Western blot analysis revealed that the combined treatment of MAG-DHA and ASA upregulated GPR-32 expression and downregulated cytosolic TNFα detection, hence preventing IκBα degradation and p65-NFκB phosphorylation. The Ca2+ sensitivity of HB was also quantified on β-escin permeabilized preparations. The presence of ASA potentiated the inhibitory effects of MAG-DHA in reducing the Ca2+ hypersensitivity triggered by IL-13 by decreasing the phosphorylation levels of the PKC-potentiated inhibitor protein-17 regulatory protein (CPI-17). In summary, MAG-DHA combined with ASA, as well as exogenously added RvD1, may represent valuable assets against critical AHR disorder.