Thioglycollate peritonitis in mice lacking C5, 5‐lipoxygenase, or p47phox: complement, leukotrienes, and reactive oxidants in acute inflammation
Thioglycollate peritonitis in mice lacking C5, 5‐lipoxygenase, or p47phox: complement, leukotrienes, and reactive oxidants in acute inflammation
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DOI：
10.1189/jlb.71.3.410
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发表时间：
2002-03
影响因子：
5.5
通讯作者：
B. Segal;D. Kuhns;L. Ding;J. Gallin;S. Holland
中科院分区：
文献类型：
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作者：
B. Segal;D. Kuhns;L. Ding;J. Gallin;S. Holland
白三烯 B4 (LTB4) 是一种易于扩散的促炎趋化因子，已被认为可以为其他介质（包括 C5a）的作用引发初始炎症反应。 5-脂氧合酶缺陷型 (5LX−/−) 和 C5 缺陷型小鼠在接受无菌刺激物巯基乙酸盐腹膜内 (IP) 攻击后，产生的腹膜白细胞增多程度仅为野生型小鼠的约 50%（P<0.005）。用特异性 5-脂氧合酶抑制剂齐留通预处理 C5− 小鼠，可将腹膜白细胞增多降低至几乎未刺激的水平，表明 LTB4 可以独立于 C5a 发挥作用。此前，LTB4 和 C5a 已在体外被证明可被超氧化物代谢物灭活。在当前的研究中，我们在慢性肉芽肿病 (CGD) 的 p47phox−/− 小鼠模型中检查了 LTB4 的命运，在该模型中，吞噬细胞 NADPH 氧化酶无法产生超氧化物。 p47phox−/− 小鼠比野生型小鼠产生更多的巯基乙酸引发的腹膜白细胞增多。用齐留通预处理可使 p47phox−/− 小鼠腹膜白细胞增多减少 76%（P<0.005），使野生型小鼠腹膜白细胞增多减少 54%（P<0.05），而用地塞米松或托拉多（环氧合酶抑制剂）预处理则没有效果。 IP LTB4（1 μg/小鼠）后，p47phox−/− 和野生型小鼠在 10 分钟和 30 分钟时恢复的总腹膜 LTB4 相似，但在 180 分钟时 p47phox−/− 小鼠中恢复的总腹膜 LTB4 大约高出五倍。这些数据表明，LTB4 和 C5a 在硫代乙醇酸盐引起的腹膜炎中具有独立但重叠的作用，并且至少白三烯成分反过来受到活性氧化剂的调节。
Leukotriene B4 (LTB4) is an easily diffusible proinflammatory chemotactic factor that has been posited to prime the initial inflammatory response for the action of other mediators, including C5a. 5‐Lipoxygenase‐deficient (5LX−/−) and C5‐deficient mice only generated about 50% as much peritoneal leukocytosis as wild‐type mice following intraperitoneal (IP) challenge with the sterile irritant, thioglycollate (P<0.005). Pretreatment of C5− mice with the specific 5‐lipoxygenase inhibitor, zileuton, reduced peritoneal leukocytosis to almost unstimulated levels, suggesting that LTB4 can act independently of C5a. Previously, LTB4 and C5a have been shown in vitro to be inactivated by metabolites of superoxide. In the current study, we examined the fate of LTB4 in the p47phox−/− mouse model of chronic granulomatous disease (CGD) in which the phagocyte NADPH oxidase is unable to produce superoxide. p47phox−/− mice generated more thioglycollate‐elicited peritoneal leukocytosis than wild‐type mice. Pretreatment with zileuton caused a 76% reduction in peritoneal leukocytosis in p47phox−/− mice (P<0.005) and a 54% reduction in wild‐type mice (P<0.05), whereas pretreatment with dexamethasone or toradol (a cyclooxygenase inhibitor) had no effect. Following IP LTB4 (1 μg/mouse), total recovered peritoneal LTB4 was similar between p47phox−/− and wild‐type mice at 10 and 30 min, but was approximately fivefold greater in p47phox−/− mice at 180 min. These data suggest that LTB4 and C5a have separate but overlapping roles in thioglycollate‐elicited peritonitis, and at least the leukotriene component is, in turn, regulated by reactive oxidants.