15-Epi-16-(para-fluorophenoxy)-lipoxin A4-methyl ester, a synthetic analogue of 15-epi-lipoxin A4, is protective in experimental ischemic acute renal failure

Lipoxins are endogenous lipoxygenase-derived eicosanoids. generated during inflammatory, hypersensitivity, and vascular events. that display vasodilatory, antiinflammatory, and pro-resolution activity. Here, we evaluated the efficacy of 15-epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester (15-epi-16-(FPhO)-LXA(4)-Me). a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A(4) in ischemic acute renal failure (ARF) in NIH Swiss mice. ARF as induced by 30-min crossclamping of renal pedicles and was associated with elevated serum creatinine, morphologic injury, polymorphonuclear leukocyte (PMN) recruitment, and increased mRNA levels for adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]) chemokines (growth regulated oncogene-1 [GRO1]), and cytokines (interleukin-1beta [IL-1beta] and IL-6) after 24-h reperfusion. A single bolus of 15-epi-16-(FPhO)-LXA(4)-Me afforded striking functional (mean +/- SEM creatinine in mg/dl: sham-operated. 0.77 +/- 0.04, ARF + vehicle, 2.49 +/- 0.19; ARF + 15-epi-16-(FPhO)-LXA(4)-Me, 0.75 +/- 0.12, P < 0.001) and morphologic protection and reduced PMN infiltration. Treatment with 15-epi-16-(FPhO)-LXA(4)-Me was also associated with loader IL-1β, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Compatible with these results. LXA(4) blunted chemoattractant-stimulated PMN migration across HK-2 renal epithelial cell monolayers in vitro, but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA(4)-Me-treated animals also displayed increased renal inRNA levels for suppressors of cytokine signaling-1 (SOCS-1) and SOCS-2, but not CIS-1, endogenous inhibitors of cytokine-elicited Jak/Stat-signaling pathways. These results indicate that 15-epi-16-(FPhO)-LXA(4)-Me is protective in renal ischemia reperfusion injury in vivo, at least partially by modulating cytokine and chemokine expression and PMN recruitment, and provides a rationale for further exploration of the efficacy of LXA(4), Structural analogues in ischemic ARF and other renal diseases.