Prostaglandins as protective mediators in Clostridium difficile infection

项目摘要 艰难梭菌感染（CDI）是一种主要的医院感染和主要可识别的原因 腹泻的症状可导致多发性CDI复发、败血症、中毒性巨结肠和死亡。 不幸的是，目前的抗生素方法并不总是能预防这些结果。该提案的重点是 一种通过利用内源性脂质信号通路来降低CDI严重程度的新方法， 最近发现的保护小鼠免受CDI的破坏性影响。 前列腺素（PGs）是由环氧合酶（考克斯）产生的内源性脂质介质。 花生四烯酸的依赖性代谢。PGE 2在炎症和感染时是丰富的， 支持结肠上皮细胞的健康，主要是通过E前列腺素（EP）4受体的连接。与此相反， 考克斯抑制剂，称为非甾体抗炎药（NSAID），是最广泛的 消费的药物可用，并已知会导致胃肠道副作用。流行病学数据链 NSAID用于各种形式的结肠炎，包括CDI。我们新的初步数据显示， 在小鼠模型中，NSAIDs可抑制随后的CDI，而常用的稳定的PGE 1类似物 （米索前列醇）可以减轻它。 芦荟素提供抗CDI保护的机制尚不清楚，但PGE 2长期以来一直是研究的热点。 已经研究了它对促进结肠上皮细胞存活的作用，在很大程度上是通过反式激活 表皮生长因子受体（EGFR）。我们有初步的数据表明PGE 2可以防止结肠炎 在C. difficile中毒，以EGFR依赖的方式。这些数据让我们 PGE 2在CDI期间通过EP 4依赖性保护胃肠道的假设 在肠上皮细胞中EGFR的反式激活，从而降低CDI的严重性。我们计划 通过（1）定义PGE 2在限制CDI严重程度中的作用和（2）阐明PGE 2-CDI的作用来检验这一假设。 刺激肠上皮细胞中的信号传导途径，这是保护免受CDI所需的。 这些研究是迈向CDI治疗和/或治疗的临床研究的关键的第一步。 利用PGE 2对结肠健康的有益作用进行预防。成功完成这些 研究将对CDI的新临床研究产生直接影响，可能为更多合理使用提供证据 高CDI风险患者中的NSAID。

PROJECT SUMMARY Clostridium difficile infection (CDI) is a leading nosocomial infection and the primary identifiable cause of antibiotic-associated diarrhea. It can lead to multiple CDI recurrences, sepsis, toxic megacolon, and death. Unfortunately, current antibiotic approaches do not always prevent these outcomes. This proposal focuses on a new approach to reducing CDI severity through exploiting an endogenous lipid signaling pathway that we recently found protects mice against the damaging effects of CDI. Prostaglandins (PGs) are endogenous lipid mediators generated by the cyclooxygenase (COX)- dependent metabolism of arachidonic acid. PGE2 is abundant at sights of inflammation and infection, and supports colon epithelial cell health primarily through ligation of the E Prostanoid (EP)4 receptor. In contrast, COX inhibitors, known as nonsteroidal anti-inflammatory drugs (NSAIDs), are among the most widely consumed drugs available and are known to cause gastrointestinal side effects. Epidemiological data link NSAID use to various forms of colitis, including CDI. Our new preliminary data show that prior exposure to NSAIDs worsens subsequent CDI in a mouse model, while a commonly-prescribed, stable PGE1 analogue (misoprostol) can alleviate it. The mechanism whereby prostaglandins provide protection against CDI is unclear, but PGE2 has long been studied for its effects on promoting colon epithelial cell survival, in large part by transactivating the epidermal growth factor receptor (EGFR). We have preliminary data to show that PGE2 prevents colon epithelial cell death in the setting of C. difficile intoxication, in an EGFR-dependent manner. These data lead us to the hypothesis that PGE2 protects the gastrointestinal tract during CDI through EP4 dependent transactivation of the EGFR in intestinal epithelial cells, thereby reducing severity of CDI. We plan to test this hypothesis by (1) defining the role of PGE2 in limiting CDI severity and (2) elucidating the PGE2- stimulated signaling pathway in intestinal epithelial cells that is required for protection against CDI. These studies are a critical first step in moving toward clinical studies of CDI treatment and/or prevention that exploit the beneficial effects of PGE2 on colon health. The successful completion of these studies will have immediate impact on new clinical studies of CDI may provide evidence for more rationale use of NSAIDs in high CDI-risk patients.