Lipoxin A attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects

BACKGROUND AND PURPOSE Lipoxin A (LXA ) is a lipid mediator involved in the resolution of inflammation. Increased levels of LXA in synovial fluid and enhanced expression of the formyl peptide receptor 2/lipoxin A 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 LXA , 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 LXA , 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)B , tumour necrosis factor (TNF)-α and the chemokine KC/CXCL1, after stimulation. The direct effect of LXA on ET-1-induced neutrophil activation and chemotaxis was evaluated by shape change and Boyden chamber assays respectively. KEY RESULTS LXA , 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, LTB and TNF-α levels were also decreased after LXA pretreatment. In vitro, ET-1-induced neutrophil chemotaxis was inhibited by LXA pretreatment. LXA treatment also inhibited ET-1-induced oedema formation and neutrophil influx into mouse knee joints. CONCLUSION AND IMPLICATION LXA exerted anti-inflammatory effects on articular inflammation through a mechanism that involved the inhibition of ET-1 expression and its effects. © 2010 The British Pharmacological Society.