Inappropriate neutrophil activation contributes to the pathogenesis of acute lung injury (ALI). Apoptosis is essential for removal of neutrophils from inflamed tissues and timely resolution of inflammation. Resolvin E1 (RvE1) is an endogenous lipid mediator derived from the ω-3 polyunsaturated fatty acid eicosapentaenoic acid that displays proresolving actions. Because the balance of prosurvival and proapoptosis signals determines the fate of neutrophils, we investigated the impact of RvE1 on neutrophil apoptosis and the outcome of neutrophil-mediated pulmonary inflammation in mice. Culture of human neutrophils with RvE1 accelerated apoptosis evoked by phagocytosis of opsonized Escherichia coli or yeast. RvE1 through the leukotriene B 4 receptor BLT1 enhanced NADPH oxidase-derived reactive oxygen species generation and subsequent activation of caspase-8 and caspase-3. RvE1 also attenuated ERK and Akt-mediated apoptosis-suppressing signals from myeloperoxidase, serum amyloid A, and bacterial DNA, shifting the balance of pro-and anti-survival signals toward apoptosis via induction of mitochondrial dysfunction. In mice, RvE1 treatment enhanced the resolution of established neutrophil-mediated pulmonary injury evoked by intratracheal instillation or i.p. administration of live E. coli or intratracheal instillation of carrageenan plus myeloperoxidase via facilitating neutrophil apoptosis and their removal by macrophages. The actions of RvE1 were prevented by the pancaspase inhibitor zVAD-fmk. These results identify a mechanism, promotion of phagocytosis-induced neutrophil apoptosis and mitigation of potent anti-apoptosis signals, by which RvE1 could enhance resolution of acute lung inflammation.leukocytes | efferocytosis | innate immunity | resolution of inflammation

The purpose of the present study was to assess whether resolvin E1 (RvE1), an anti-inflammatory mediator derived from eicosapentaenoic acid, would limit myocardial infarct size in the rat. The H9c2 cell line was used to assess whether RvE1 has direct protective effects on cardiomyocytes. In in vivo experiments, Male Sprague-Dawley rats underwent 30 min of ischemia/4 h of reperfusion. Before reperfusion, rats received intravenous RvE1 (0, 0.03, 0.1, or 0.3mg/kg). In in vitro experiments, H9c2 cells were incubated with RvE1 (0, 1, 10, 100, or 1000 nM). Cells were subjected to 18 h of incubation under normoxic conditions, 16 h of hypoxia, or 16 h of hypoxia and 2 h of reoxygenation. In vivo, RvE1 dose dependently reduced infarct size (30.7 ± 1.7% of the area at risk in the control group and 29.1 ± 1.6%, 14.7 ± 1.3%, and 9.0 ± 0.6% in the 0.03, 0.1, and 0.3 mg/kg groups, respectively, P < 0.001). In vitro, RvE1 increased viability and decreased apoptosis in a dose-dependent fashion in cells exposed to hypoxia or hypoxia/reoxygenation. A maximal effect was achieved at a concentration of 100 nM. RvE1 augmented phosphoinositide 3-kinase activity, attenuated caspase-3 activity, and augmented calcium-dependent nitric oxide synthase activity in cells exposed to hypoxia or hypoxia/reoxygenation. RvE1 increased Akt, ERK1/2, and endothelial nitric oxide synthase phosphorylation and attenuated the levels of activated caspase-3 and phosphorylated p38 levels. AG-1478, an EGF receptor tyrosine kinase inhibitor, blocked the protective effect of RvE1 both in vivo and in vitro and attenuated the RvE1-induced increase in Akt and ERK1/2 phosphorylation. In conclusion, RvE1, an anti-inflammatory mediator derived from eicosapentaenoic acid, has a direct protective effect on cardiomyocytes against ischemia-reperfusion injury and limits infarct size when administered intravenously before reperfusion.

Stromal keratitis (SK) is a chronic immunopathological lesion of the eye caused by herpes simplex virus-1 (HSV-1) infection and a common cause of blindness in humans. The inflammatory lesions are primarily perpetuated by neutrophils with the active participation of CD4+ T cells. Therefore, targeting these immune cell types represents a potentially valuable form of therapy to reduce the severity of disease. Resolvin E1 (RvE1), an endogenous lipid mediator, was shown to promote resolution in several inflammatory disease models. In the present report, we determined if RvE1 administration begun at different times after ocular infection of mice with HSV could influence the severity of SK lesions. Treatment with RvE1 significantly reduced the extent of angiogenesis and SK lesions that occurred. RvE1 treated mice had fewer numbers of inflammatory cells that included Th1 and Th17 cells as well as neutrophils in the cornea. The mechanisms by which RvE1 acts appear to be multiple. These included reducing the influx of neutrophils and pathogenic CD4+ T cells, increasing production of the anti-inflammatory cytokine IL-10, and inhibitory effects on the production of pro-inflammatory mediators and molecules such as IL-6, IFN-γ, IL-17, KC, VEGF-A, MMP-2 and MMP-9, that are involved in corneal neovascularization and SK pathogenesis. These findings are the first to show that RvE1 treatment could represent a novel approach to control lesion severity in a virally induced immunopathological disease.

Purpose: Dry eye (DE) is a common ocular surface disease, particularly among women and the elderly, with chronic symptoms of eye irritation and, in severe cases, blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Resolvin E1 (RvE1; RX-10001) is an endogenous mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid and is involved in inflammation resolution and tissue protection. Here we investigated the role of RvE1 in a DE mouse model. Methods: Thirteen-to 14-week-old female BALB/C mice were exposed to desiccating conditions. One week after DE exposure, animals were treated topically with drug or vehicle 4 times per day for an additional week. Controls were nontreated animals placed in a normal environment. Schirmer's test was performed before treatment initiation and at days 2 and 4 after treatment. Density of corneal epithelial cells was analyzed in vivo using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT-II). Corneas were processed using Western blot analysis and immunofluorescence examination. Results: Schirmer's test showed a significant decrease in tear production in DE compared with controls. There was no change at 2 and 4 days after treatment with the vehicle, but a significant increase was observed at 2 and 4 days in the RvE1-treated group. The density of the superficial epithelial cells showed a significant decrease after DE compared with controls, which increased after 7 days of RvE1 treatment. Western blot analysis showed that asmooth muscle actin and cyclooxygenase-2 (COX-2) expression were strongly upregulated after DE and decreased after 7 days of RvE1 treatment. Immunofluorescence confirmed strong positive staining of a-smooth muscle actin and COX-2 in stroma and/or in epithelia after DE, which decreased with RvE1 treatment. The percentage of infiltrating CD4þ T cells and CD11b þ cells decreased after RvE1 treatment when compared with DE. Conclusion: RvE1 promotes tear production, corneal epithelial integrity, and a decrease in inflammatory inducible COX-2. In the stroma, RvE1 inhibits keratocyte transformation to myofibroblasts and lowers the number of monocytes/macrophages in this DE mouse model. These results suggest that RvE1 and similar resolvin analogs have therapeutic potential in the treatment of DE.

RvE1 attenuates atherogenesis both alone and on top of a statin. The local effects of RvE1 are demonstrated by the modulated aortic expression of genes involved in inflammatory and immune responses, without altering plasma cholesterol or circulating SAA.