Wada K, Qiu F H, Stahl G L, Serhan C N
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Hematother Stem Cell Res. 2001 Feb;10(1):75-9. doi: 10.1089/152581601750098273.
Regulation of neutrophil (PMN) trafficking by soluble mediators is a critical component in the outcome of host defense, inflammation resolution, and neutrophil-mediated tissue injury. Elucidation of the endogenous mediators that protect tissues from excess leukocyte traffic and aberrant PMN activation that can lead to tissue damage and chronic inflammation is of considerable interest, especially the endogenous mechanisms of anti-inflammation. To this end, we recently uncovered two new classes of mediators: inosine monophosphate (IMP) and aspirin-triggered 15(R)-epimers of native lipoxin A(4). Here, we examined the combined actions of both classes of compounds in regulating key events in neutrophil trafficking. Neutrophil rolling in mouse microvessels was inhibited by both IMP or 5S,6R,15R-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid (15-epi-LXA(4)) in a concentration-dependent fashion. When combined, IMP (300 nM) and 15-epi-LX (10 nM) demonstrated additive inhibition of neutrophil rolling in microvessels. IMP and 15-epi-LX also significantly inhibited tumor necrosis factor-alpha (TNF-alpha)-induced neutrophil accumulation into the mouse air pouch in a dose-dependent manner. Again, the combination of low dose IMP (10 microg) and LX analog (5 microg) gave additive inhibition of neutrophil accumulation in this model. These results demonstrate the inhibition of neutrophil trafficking in two separate models by two different classes of small endogenous molecules. The additive inhibition by IMP and aspirin-triggered LX may represent key pathways that protect and resolve inflammatory responses that could be harnessed for treatment.
可溶性介质对中性粒细胞（PMN）迁移的调节是宿主防御、炎症消退以及中性粒细胞介导的组织损伤结果中的关键组成部分。阐明保护组织免受过多白细胞迁移以及可导致组织损伤和慢性炎症的异常PMN激活影响的内源性介质具有重要意义，尤其是抗炎的内源性机制。为此，我们最近发现了两类新的介质：肌苷单磷酸（IMP）和阿司匹林触发的天然脂氧素A4的15（R）-差向异构体。在此，我们研究了这两类化合物在调节中性粒细胞迁移关键事件中的联合作用。IMP或5S，6R，15R-三羟基-7,9,13-反式-11-顺式-二十碳四烯酸（15-表-LXA4）均以浓度依赖性方式抑制小鼠微血管中的中性粒细胞滚动。当联合使用时，IMP（300 nM）和15-表-LX（10 nM）对微血管中的中性粒细胞滚动表现出相加抑制作用。IMP和15-表-LX还以剂量依赖性方式显著抑制肿瘤坏死因子-α（TNF-α）诱导的中性粒细胞在小鼠气囊中的积聚。同样，低剂量IMP（10μg）和LX类似物（5μg）的联合使用在该模型中对中性粒细胞积聚产生相加抑制作用。这些结果表明，两类不同的内源性小分子在两个独立模型中均抑制了中性粒细胞迁移。IMP和阿司匹林触发的LX的相加抑制作用可能代表了保护和解决炎症反应的关键途径，有望用于治疗。
