Opposing and hierarchical roles of leukotrienes in local innate immune versus vascular responses in a model of sepsis
Opposing and hierarchical roles of leukotrienes in local innate immune versus vascular responses in a model of sepsis
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DOI：
10.4049/jimmunol.174.3.1616
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发表时间：
2005-02-01
影响因子：
4.4
通讯作者：
Peters-Golden, M
中科院分区：
文献类型：
--
作者：
Benjamim, CF;Canetti, C;Peters-Golden, M
5-脂氧合酶（5-LO）衍生的白三烯（LT）影响局部先天免疫和血管反应，但在脓毒症中对这两个过程的影响的相对重要性尚不清楚。在盲肠结扎和穿孔腹膜炎严重脓毒症模型中，5-LO-/-小鼠显示腹膜中性粒细胞积聚减少，腹膜腔中细菌数量增加。尽管这种局部先天免疫的损害，无效小鼠表现出显着的改善生存，这种保护也被视为在野生型动物与LT合成抑制剂MK 886治疗。在用半胱氨酰-LT受体拮抗剂MK 571治疗的小鼠中也观察到严重脓毒症的存活优势，但用LTB 4受体拮抗剂CP 105，696治疗的小鼠中未观察到。5-LO-/-小鼠的保护作用与血管渗漏和血清乳酸水平降低有关。此外，用MK 571处理的野生型小鼠表现出更少的脓毒症诱导的低血压。这些数据证明了半胱氨酰-LT对先天免疫与血液动力学应答的相反作用，证明了对局部免疫的保护作用和对脉管系统的有害作用。他们还建议用半胱氨酰-LT阻断靶向败血症中的血管事件的可能治疗效用。
The 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) influence both local innate immunity and vascular responses, but the relative importance of effects on these two processes in sepsis is unknown. In a cecal ligation and puncture model of peritonitis with severe sepsis, 5-LO-/- mice showed a reduction in peritoneal neutrophil accumulation and an increase in the number of bacteria in the peritoneal cavity. Despite this impairment of local innate immunity, the null mice exhibited a marked improvement in survival, and this protection was also seen in wild-type animals treated with the LT synthesis inhibitor MK 886. A survival advantage in severe sepsis was also observed in mice treated with the cysteinyl-LT receptor antagonist MK 571, but not with the LTB4 receptor antagonist CP 105, 696. Protection in the 5-LO-/- mice was associated with reduced vascular leak and serum lactate levels. Moreover, wild-type mice treated with MK 571 exhibited less sepsis-induced hypotension. These data demonstrate opposing effects of cysteinyl-LTs on innate immune vs hemodynamic responses, demonstrating protective effects on local immunity and deleterious effects on the vasculature. They also suggest the possible therapeutic utility of targeting vascular events in sepsis with cysteinyl-LT blockade.