Department of Cell Biology, University of Medicine and Dentistry, New Jersey-SOM, Stratford, New Jersey 08084, USA.
Shock. 2011 Oct;36(4):410-6. doi: 10.1097/SHK.0b013e31822798c1.
Sepsis is characterized by systemic inflammation with release of a large amount of inflammatory mediators. If sustained, this inflammatory response can lead to multiple organ failure and/or immunoparalysis. In the latter condition, the host may be susceptible to opportunistic infections or be unable to clear existing infections. Therefore, it is potentially beneficial to resolve inflammation by reducing inflammation without compromising host defense. We examined the effect of lipoxin A4 (LXA4), a compound with inflammatory resolution properties, in the cecal ligation and puncture (CLP) model of sepsis. Cecal ligation and puncture rats were given either saline or LXA4 (40 μg/kg, i.p.) 5 h after surgery. Lipoxin A4 administration increased 8-day survival of CLP rats, which lived longer than 48 h, and attenuated tissue injury after 8 days. Therefore, we investigated the effects of LXA4 on systemic inflammation and bacterial load 48 h after CLP sepsis. Plasma IL-6, monocyte chemotactic protein 1, and IL-10 levels were reduced in LXA4-treated rats compared with CLP rats given saline vehicle. Lipoxin A4 reduced phosphorylation of the p65 subunit of nuclear factor κB (NF-κB) at serines 536 and 468 in peritoneal macrophages, suggesting that LXA4 reduced production of proinflammatory mediators through an NF-κB-mediated mechanism. Lipoxin A4 reduced blood bacterial load and increased peritoneal macrophage number without affecting phagocytic ability, suggesting that LXA4 reduced blood bacterial load by enhancing macrophage recruitment. It also suggests that LXA4 reduced systemic inflammation and NF-κB activation without compromising host defense. Increased macrophage recruitment was in part due to a direct effect of LXA4 as LXA4 increased peritoneal macrophage recruitment in sham controls and partly due to reduced production of IL-10 as LXA4 decreased macrophage IL-10 release (a known inhibitor of macrophage migration) after CLP. The results suggest that LXA4 increased survival in sepsis by simultaneously reducing systemic inflammation as well as bacterial spread.
脓毒症的特征是全身炎症伴有大量炎症介质的释放。如果这种炎症反应持续存在，可能会导致多器官衰竭和/或免疫麻痹。在后一种情况下，宿主可能容易发生机会性感染，或者无法清除现有的感染。因此，通过减轻炎症而不损害宿主防御来解决炎症反应可能是有益的。我们研究了脂氧素 A4（LXA4），一种具有炎症消退特性的化合物，在盲肠结扎和穿刺（CLP）脓毒症模型中的作用。CLP 手术后 5 小时，盲肠结扎和穿刺大鼠给予生理盐水或 LXA4（40μg/kg，腹腔注射）。LXA4 给药增加了 CLP 大鼠的 8 天存活率，这些大鼠存活时间超过 48 小时，并减轻了 8 天后的组织损伤。因此，我们研究了 LXA4 对 CLP 脓毒症 48 小时后全身炎症和细菌负荷的影响。与给予生理盐水载体的 CLP 大鼠相比，LXA4 处理的大鼠血浆白细胞介素 6（IL-6）、单核细胞趋化蛋白 1 和白细胞介素 10 水平降低。LXA4 减少了腹腔巨噬细胞中核因子 κB（NF-κB）p65 亚基丝氨酸 536 和 468 的磷酸化，表明 LXA4 通过 NF-κB 介导的机制减少了促炎介质的产生。LXA4 降低了血细菌负荷并增加了腹腔巨噬细胞数量，而不影响吞噬能力，这表明 LXA4 通过增强巨噬细胞募集来降低血细菌负荷。这也表明 LXA4 降低了全身炎症和 NF-κB 激活，而不损害宿主防御。巨噬细胞募集的增加部分归因于 LXA4 的直接作用，因为 LXA4 增加了 sham 对照组腹腔巨噬细胞的募集，部分归因于 LXA4 降低了巨噬细胞白细胞介素 10 的释放（已知的巨噬细胞迁移抑制剂）后 CLP。结果表明，LXA4 通过同时减少全身炎症和细菌扩散，增加了脓毒症的存活率。
