17-oxo-DHA displays additive anti-inflammatory effects with fluticasone propionate and inhibits the NLRP3 inflammasome.

17-oxo-DHA is a bioactive electrophilic ?,?-unsaturated keto-derivative of the omega-3 fatty acid docosahexaenoic acid (DHA) that is generated by cyclooxygenase-2 in activated macrophages. Herein the anti-inflammatory efficacy of 17-oxo-DHA alone or in combination with the steroid fluticasone propionate (FP) (measured as suppression of LPS-induced TNF? and IL-1? release) was evaluated in LPS-stimulated peripheral blood mononuclear cells (PBMCs) from COPD patients and healthy controls. Our primary goals were to assess (i) whether the PBMCs isolated from the two study groups responded differently to LPS and to FP, and (ii) whether 17-oxo-DHA could enhance FP efficacy. Data herein reported show that PBMCs from COPD patients released significantly higher level of IL-1? and TNF? in response to LPS, and that FP was unable to bring cytokine levels back to baseline, especially in the COPD group. 17-oxo-DHA, when added in combination with the steroid, showed synergistic effects with FP and significantly enhanced the steroid efficacy in both study groups. Both FP and 17-oxo-DHA acted at transcriptional level. In addition, 17-oxo-DHA was able to block IL-1? release by acting at post-transcriptional level via inflammasome inhibition. Overall, our data support that 17-oxo-DHA effectively counteracts inflammation and, when administered in combination with FP, provides more effective anti-inflammatory actions in LPS-stimulated PBMCs from COPD and control subjects by acting via multiple mechanisms. This may have important implications especially in the case of exacerbations and supports that 17-oxo-DHA is a promising compound for the development of new drugs for steroid resistant COPD.