Lipoxin A4 attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects
Lipoxin A4 attenuates zymosan-induced arthritis by modulating endothelin-1 and its effects
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DOI：
10.1111/j.1476-5381.2010.00950.x
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发表时间：
2010-10-01
影响因子：
7.3
通讯作者：
Henriques, M. G.
中科院分区：
文献类型：
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作者：
Conte, F. P.;Menezes-de-Lima, O., Jr.;Henriques, M. G.
背景与技术脂氧素A（4）（LXA（4））是一种参与炎症消退的脂质介质。已经报道了类风湿性关节炎患者滑液中LXA（4）水平的增加和滑膜组织中甲酰基肽受体2/脂氧素A（4）受体（FPR 2/ALX）表达的增强。内皮素（Endothelins，ET）在急性关节炎性反应中起着重要的促炎作用。实验方法在酵母多糖诱导的关节炎的小鼠模型中研究了LXA（4）、BML-111（FPR 2/ALX受体激动剂）和乙酰水杨酸（阿萨）治疗前和治疗后的抗炎作用。通过检查膝关节水肿、滑膜腔中的中性粒细胞积聚、以及刺激后前原ET-1 mRNA、白三烯（LT）B-4、肿瘤坏死因子（TNF）-α和趋化因子KC/CXCL 1的水平来评估关节炎症。LXA（4）对内皮素（ET-1）诱导的中性粒细胞活化和趋化作用的直接影响分别用形态改变和Boyden小室实验来评价。LXA（4）预处理后，酵母多糖诱导的preproET-1 mRNA、KC/CXCL 1、LTB 4和TNF-α水平也降低。在体外，LXA 4预处理可抑制ET-1诱导的中性粒细胞趋化性。结论与意义LXA（4）通过抑制ET-1的表达及其作用，发挥抗炎作用。
BACKGROUND AND PURPOSELipoxin A(4) (LXA(4)) is a lipid mediator involved in the resolution of inflammation. Increased levels of LXA(4) in synovial fluid and enhanced expression of the formyl peptide receptor 2/lipoxin A(4) 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(4), during the acute phase of zymosan-induced arthritis, focusing on the modulation of ET-1 expression and its effects.EXPERIMENTAL APPROACHThe anti-inflammatory effects of LXA(4), 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-4, tumour necrosis factor (TNF)-alpha and the chemokine KC/CXCL1, after stimulation. The direct effect of LXA(4) on ET-1-induced neutrophil activation and chemotaxis was evaluated by shape change and Boyden chamber assays respectively.KEY RESULTSLXA(4), 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-alpha levels were also decreased after LXA(4) pretreatment. In vitro, ET-1-induced neutrophil chemotaxis was inhibited by LXA4 pretreatment. LXA(4) treatment also inhibited ET-1-induced oedema formation and neutrophil influx into mouse knee joints.CONCLUSION AND IMPLICATIONLXA(4) exerted anti-inflammatory effects on articular inflammation through a mechanism that involved the inhibition of ET-1 expression and its effects.