BACKGROUND AND PURPOSE Lipoxin A4 (LXA4) is a lipid mediator involved in the resolution of inflammation. Increased levels of LXA4 in synovial fluid and enhanced expression of the formyl peptide receptor 2/lipoxin A4 receptor (FPR2/ALX) in the synovial tissues of rheumatoid arthritis patients have been reported. Endothelins (ETs) play a pivotal pro‐inflammatory role in acute articular inflammatory responses. Here, we evaluated the anti‐inflammatory role of LXA4, during the acute phase of zymosan‐induced arthritis, focusing on the modulation of ET‐1 expression and its effects. EXPERIMENTAL APPROACH The anti‐inflammatory effects of LXA4, BML‐111 (agonist of FPR2/ALX receptors) and acetylsalicylic acid (ASA) pre‐ and post‐treatments were investigated in a murine model of zymosan‐induced arthritis. Articular inflammation was assessed by examining knee joint oedema; neutrophil accumulation in synovial cavities; and levels of prepro‐ET‐1 mRNA, leukotriene (LT)B4, tumour necrosis factor (TNF)‐α and the chemokine KC/CXCL1, after stimulation. The direct effect of LXA4 on ET‐1‐induced neutrophil activation and chemotaxis was evaluated by shape change and Boyden chamber assays respectively. KEY RESULTS LXA4, BML‐111 and ASA administered as pre‐ or post‐treatment inhibited oedema and neutrophil influx induced by zymosan stimulation. Zymosan‐induced preproET‐1 mRNA, KC/CXCL1, LTB4 and TNF‐α levels were also decreased after LXA4 pretreatment. In vitro, ET‐1‐induced neutrophil chemotaxis was inhibited by LXA4 pretreatment. LXA4 treatment also inhibited ET‐1‐induced oedema formation and neutrophil influx into mouse knee joints. CONCLUSION AND IMPLICATION LXA4 exerted anti‐inflammatory effects on articular inflammation through a mechanism that involved the inhibition of ET‐1 expression and its effects.
Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae. LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (LXA4 and BML-111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h) sepsis were studied. Sepsis induced an early increase in LXA4, FPR2/ALX lung expression, local and systemic infection and inflammation, and mortality. Treatment with BOC-2 in early sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and 15-lipoxygenase in early sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic LXA4 or BML-111 in early sepsis decreased cell migration and worsened the infection. In late sepsis, treatment with BOC-2 had no effect, but LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator LXA4 and its receptor FPR2/ALX levels were increased in the early phase of sepsis, contributing to the septic inflammatory dysregulation. In addition, LXA4 has a dual role in sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with LXA4 system may be a new therapeutic avenue to treat sepsis.
Lipoxin A 4 (LXA 4 ) is a lipid mediator that plays an important role in inflammation resolution. We assessed the anti-inflammatory effect of LXA 4 on endotoxin-induced uveitis (EIU) in rats. The inflammatory cell number and levels of tumor necrosis factor-␣ (TNF-␣), interleukin-1 (IL-1), prostaglandin E 2 (PGE 2 ), and protein, as well as expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), in the anterior chamber of the eye were determined 24 h after lipopolysaccharide (LPS; 200 g/paw) intradermal injection. The immunohistochemical reactivities of nuclear factor-B (NF-B) and c-Jun were also examined. Topical LXA 4 (1-10 ng/eye) pretreatment decreased the number of inflammatory cells and the protein leakage into the aqueous humor (AqH). In addition, topical LXA 4 (10 ng/eye) inhibited the LPS-induced production of IL-1, TNF-␣, and PGE 2 , and expression of COX-2 and VEGF. A decreased activation of NF-B and c-Jun was also found in LXA 4 -treated eyes. It is very interesting that an anti-inflammatory effect was achieved even when LXA 4 (10 ng/eye) was applied topically after LPS challenge, as indicated by the reduction in the cellular and protein extravasations into the AqH. Moreover, topical treatment of corticosteroid prednisolone (200 g/eye) beginning before or after LPS injection reduced all of the molecular and biochemical alterations promoted on EIU rats in an efficacy similar to that of LXA 4 . Together, the present results provide clear evidence that pharmacological activation of LXA 4 signaling pathway potently reduces the EIU in rats. Therefore, LXA 4 stable analogs could represent promising agents for the management of ocular inflammatory diseases.
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