Misoprostol impairs female reproductive tract innate immunity against Clostridium sordelli
Misoprostol impairs female reproductive tract innate immunity against Clostridium sordelli
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DOI：
10.4049/jimmunol.180.12.8222
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发表时间：
2008-06-15
影响因子：
4.4
通讯作者：
Peters-Golden, Marc
中科院分区：
文献类型：
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作者：
Aronoff, David M.;Hao, Yibai;Peters-Golden, Marc
本文报告了米非司酮（也称为RU-486）与米索前列醇联合用药流产后并发索氏梭菌肠炎急性休克的死亡病例。这种意外并发症的发病机制仍然是个谜。米索前列醇是PGE（2）的药物模拟物，PGE是先天免疫的内源性抑制剂。临床C。sordelli感染与阴道内施用米索前列醇有关，表明子宫内高浓度的米索前列醇损害了针对C. sordelli。我们对C进行了建模。在大鼠中进行Sordelli pancretis以验证这一假设。米索前列醇的宫内给药而非胃内给药显著加重了C. Sordelli子宫感染和体内细菌清除受损。米索前列醇也减少感染期间子宫内TNF-α的产生。子宫内注射米索前列醇并没有增加阴道细菌卷曲乳杆菌感染的死亡率。在体外，米索前列醇抑制C. sordelli或肽聚糖攻击，损害C. sordelli，并抑制子宫上皮细胞人β-防御素的表达。米索前列醇的这些免疫抑制作用与G.蛋白偶联的E前列腺素（EP）受体EP 2和EP 4（巨噬细胞）或单独的EN（子宫上皮细胞）。我们的数据为流产后脓毒症导致死亡提供了一个新的解释，也表明PGE（2）在妊娠期间生殖道内的产生被夸大，可能是更常见的妊娠子宫感染发病机制的一个重要决定因素。
Fatal cases of acute shock complicating Clostridium sordellii endometritis following medical abortion with mifepristone (also known as RU-486) used with misoprostol were reported. The pathogenesis of this unexpected complication remains enigmatic. Misoprostol is a pharmacomimetic of PGE(2), an endogenous suppressor of innate immunity. Clinical C. sordelli infections were associated with intravaginal misoprostol administration, suggesting that high misoprostol concentrations within the uterus impair immune responses against C. sordelli. We modeled C. sordelli endometritis in rats to test this hypothesis. The intrauterine but not the intragastric delivery of misoprostol significantly worsened mortality from C. sordelli uterine infection, and impaired bacterial clearance in vivo. Misoprostol also reduced TNF-alpha production within the uterus during infection. The intrauterine injection of misoprostol did not enhance mortality from infection by the vaginal commensal bacterium Lactobacillus crispatus. In vitro, misoprostol suppressed macrophage TNF-a and chemokine generation following C. sordelli or peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordelli, and inhibited uterine epithelial cell human beta-defensin expression. These immunosuppressive effects of misoprostol, which were not shared by mifepristone, correlated with the activation of the G. protein-coupled E prostanoid (EP) receptors EP2 and EP4 (macrophages) or EN alone (uterine epithelial cells). Our data provide a novel explanation for postabortion sepsis leading to death and also suggest that PGE(2), in which production is exaggerated within the reproductive tract during pregnancy, might be an important causal determinant in the pathogenesis of more common infections of the gravid uterus.