Mitchell Siobhan, Thomas Graham, Harvey Killeen, Cottell David, Reville Keira, Berlasconi Giovanni, Petasis Nicos A, Erwig Lars, Rees Andrew J, Savill John, Brady Hugh R, Godson Catherine
Centre for Molecular Inflammation and Vascular Research, Mater Misericordiae Hospital and Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Ireland.
J Am Soc Nephrol. 2002 Oct;13(10):2497-507. doi: 10.1097/01.asn.0000032417.73640.72.
Lipoxins (LX) are eicosanoids with antiinflammatory activity in glomerulonephritis (GN) and inflammatory diseases, hypersensitivity, and ischemia reperfusion injury. It has been demonstrated that LXA(4) stimulates non-phlogistic phagocytosis of apoptotic polymorphonuclear neutrophils (PMN) by monocyte-derived macrophages (Mphi) in vitro, suggesting a role for LX as endogenous pro-resolution lipid mediators. It is here reported that LXA(4), LXB(4), the aspirin-triggered LX (ATL) epimer, 15-epi-LXB(4), and a stable synthetic analogue 15(R/S)-methyl-LXA(4) stimulate phagocytosis of exogenously administered excess apoptotic PMN by macrophages (M phi) in vivo in a classic model of acute inflammation, namely thioglycollate-induced peritonitis. Significant enhancement of phagocytosis in vivo was observed with 15-min exposure to LX and with intraperitoneal doses of LXA(4), LXB(4), 15(R/S)-methyl-LXA(4), and 15-epi-LXB(4) of 2.5 to 10 micro g/kg. Non-phlogistic LX-stimulated phagocytosis by M phi was sensitive to inhibition of PKC and PI 3-kinase and associated with increased production of transforming growth factor-beta(1) (TGF-beta(1)). LX-stimulated phagocytosis was not inhibited by phosphatidylserine receptor (PSR) antisera and was abolished by prior exposure of M phi to beta 1,3-glucan, suggesting a novel M phi-PMN recognition mechanism. Interestingly, the recently described peptide agonists of the LXA(4) receptor (MYFINITL and LESIFRSLLFRVM) stimulated phagocytosis through a process associated with increased TGF-beta(1) release. These data provide the first demonstration that LXA(4), LXB(4), ATL, and LX stable analogues rapidly promote M phi phagocytosis of PMN in vivo and support a role for LX as rapidly acting, pro-resolution signals in inflammation. Engagement of the LXR by LX generated during cell-cell interactions in inflammation and by endogenous LXR peptide agonists released from distressed cells may be an important stimulus for clearance of apoptotic cells and may be amenable to pharmacologic mimicry for therapeutic gain.
脂氧素（LX）是一类在肾小球肾炎（GN）、炎症性疾病、超敏反应及缺血再灌注损伤中具有抗炎活性的类二十烷酸。已有研究表明，LXA(4) 在体外可刺激单核细胞衍生的巨噬细胞（Mphi）对凋亡多形核中性粒细胞（PMN）进行非炎性吞噬，提示LX作为内源性促炎症消退的脂质介质发挥作用。本文报道，在急性炎症的经典模型即巯基乙酸盐诱导的腹膜炎中，LXA(4)、LXB(4)、阿司匹林触发的LX（ATL）差向异构体15-表-LXB(4) 以及稳定的合成类似物15(R/S)-甲基-LXA(4) 可刺激巨噬细胞（M phi）在体内对体外给予的过量凋亡PMN进行吞噬。在体内，给予LX 15分钟以及腹腔注射剂量为2.5至10μg/kg的LXA(4)、LXB(4)、15(R/S)-甲基-LXA(4) 和15-表-LXB(4) 后，观察到吞噬作用显著增强。M phi介导的非炎性LX刺激的吞噬作用对蛋白激酶C（PKC）和磷脂酰肌醇3-激酶（PI 3-激酶）的抑制敏感，并与转化生长因子-β1（TGF-β1）产生增加相关。LX刺激的吞噬作用不受磷脂酰丝氨酸受体（PSR）抗血清的抑制，且在M phi预先暴露于β1,3-葡聚糖后被消除，提示存在一种新的M phi-PMN识别机制。有趣的是，最近描述的LXA(4) 受体肽激动剂（MYFINITL和LESIFRSLLFRVM）通过与TGF-β1释放增加相关的过程刺激吞噬作用。这些数据首次证明，LXA(4)、LXB(4)、ATL和LX稳定类似物可在体内迅速促进M phi对PMN的吞噬，并支持LX作为炎症中快速起效的促炎症消退信号发挥作用。炎症中细胞间相互作用产生的LX以及受损细胞释放的内源性LXR肽激动剂与LXR的结合，可能是清除凋亡细胞的重要刺激因素，并且可能适用于药物模拟以获得治疗益处。
