MAG ‐ DPA curbs inflammatory biomarkers and pharmacological reactivity in cytokine‐triggered hyperresponsive airway models

Abstract

Bronchial inflammation contributes to a sustained elevation of airway hyperresponsiveness (AHR) in asthma. Conversely, omega‐3 fatty acid derivatives have been shown to resolve inflammation in various tissues. Thus, the effects of docosapentaenoic acid monoacylglyceride (MAG‐DPA) were assessed on inflammatory markers and reactivity of human distal bronchi as well as in a cultured model of guinea pig tracheal rings. Human bronchi were dissected and cultured for 48 h with 10 ng/mL TNF‐α or IL‐13. Guinea pig tracheas were maintained in organ culture for 72 h which was previously shown to trigger spontaneous AHR. All tissues were treated with increasing concentrations of MAG‐DPA (0.1, 0.3, and 1 μmol/L). Pharmacomechanical reactivity, Ca2+ sensitivity, and western blot analysis for specific phosphoproteins and transcription factors were performed to assess the effects of both cytokines, alone or in combination with MAG‐DPA, on human and guinea pig airway preparations. Although 0.1 μmol/L MAG‐DPA did not significantly reduce inflammatory biomarkers, the higher concentrations of MAG‐DPA (0.3 and 1 μmol/L) blunted the activation of the TNF‐α/NF κB pathway and abolished COX‐2 expression in human and guinea pig tissues. Moreover, 0.3 and 1 μmol/L MAG‐DPA consistently decreased the Ca2+ sensitivity and pharmacological reactivity of cultured bronchial explants. Furthermore, in human bronchi, IL‐13‐stimulated phosphorylation of CPI‐17 was reversed by 1 μmol/L MAG‐DPA. This effect was further amplified in the presence of 100 μmol/L aspirin. MAG‐DPA mediates antiphlogistic effects by increasing the resolution of inflammation, while resetting Ca2+ sensitivity and contractile reactivity.

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

“…Such findings are in keeping with a previous report demonstrating the blunting of the TNF-α/NFκB pathway by RvD 1 in IL-13 pre-treated human bronchi [21]. Similarly, MAG-EPA and MAG-DPA were furthermore shown to normalise the NFκB and AP-1 signalling pathways in guinea pig tracheal rings pre-treated with exogenous TNF-α [36, 37]. In addition to corroborating observations in a previous study demonstrating the involvement of RvD 1 in the inactivation of the 5-lipoxygenase pathway in macrophages [22], our data obtained in LTD 4 -treated human bronchi also reveal that TNF-α mediated activation of the 5-LOX/CysLTR1 pathway is normalised upon RvD 2 treatments.…”