Prostaglandins as protective mediators in Clostridium difficile infection

前列腺素作为艰难梭菌感染的保护介质

• 批准号: 9316517
• 负责人: David M Aronoff
• 金额: $ 19.75万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316517
• 关键词: Address; Adverse effects; Alprostadil; Antibiotic Therapy; Antibiotics; Arachidonic Acids; Bacteria; Blood Circulation; Cell Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Clinical; Clinical Research; Clostridium difficile; Colitis; Colon; Communicable Diseases; Cyclooxygenase Inhibitors; Data; Development; Diarrhea; Dinoprostone; Drug usage; EP4 receptor; Epidermal Growth Factor Receptor; Epithelial Cells; Exposure to; Gastrointestinal tract structure; Genes; Goals; Health; Hospitals; Infection; Inflammation; Intestines; Intoxication; Knowledge; Large Intestine; Lead; Ligands; Ligation; Link; Lipids; Mediating; Mediator of activation protein; Misoprostol; Mus; Non-Steroidal Anti-Inflammatory Agents; Nosocomial Infections; Outcome; Patient risk; Patient-Focused Outcomes; Pharmaceutical Preparations; Pharmacology; Physiological Processes; Prevention; Probiotics; Prostaglandin E Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Receptor Activation; Receptor Signaling; Recurrence; Regulation; Research; Resistance; Risk; Role; Sepsis; Severities; Signal Pathway; Signal Transduction; Synthetic Prostaglandins; Testing; Therapeutic; Toxic Megacolon; Transactivation; Transcriptional Regulation; Vision; WFDC2 gene; Work; Wound Healing; analog; base; cost effective; eicosanoid metabolism; epidemiologic data; experimental study; fecal transplantation; gastrointestinal; gut microbiome; improved; intestinal epithelium; lipid mediator; migration; mouse PGE synthase 1; mouse model; novel strategies; prevent; receptor; success; therapeutic target

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.

项目摘要 艰难梭菌感染（CDI）是主要的医院感染，是可识别的主要原因 抗生素相关的腹泻。它可能导致多种CDI复发，败血症，有毒的巨型巨型和死亡。 不幸的是，当前的抗生素方法并不总是阻止这些结果。该提议重点 通过利用内源性脂质信号通路来降低CDI严重程度的一种新方法 最近发现保护小鼠免受CDI的破坏作用。 前列腺素（PGS）是由环氧酶（COX）产生的内源性脂质介质 - 花生四烯酸的依赖性代谢。 PGE2在炎症和感染的视线中很丰富，并且 主要通过结扎前列腺素（EP）4受体支持结肠上皮细胞健康。相比之下， COX抑制剂，称为非甾体类抗炎药（NSAID），是最广泛的 食用药物可用，已知会引起胃肠道副作用。流行病学数据链接 NSAID用于包括CDI在内的各种形式的结肠炎。我们的新初步数据表明，事先接触 NSAID在鼠标模型中加剧了随后的CDI，而通常处方稳定的PGE1模拟 （米索前列醇）可以减轻它。 前列腺素提供针对CDI的机制尚不清楚，但PGE2长期很长 研究了其对促进结肠上皮细胞存活的影响，在很大程度上是通过反式激活 表皮生长因子受体（EGFR）。我们有初步数据，以表明PGE2可防止结肠 艰难梭菌中毒的上皮细胞死亡，以EGFR依赖性方式。这些数据导致我们 假设PGE2通过EP4依赖性CDI期间保护胃肠道 EGFR在肠上皮细胞中的反式激活，从而降低了CDI的严重程度。我们计划 通过（1）定义PGE2在限制CDI严重程度和（2）阐明PGE2-的作用来检验这一假设。 肠上皮细胞中刺激的信号通路是防止CDI所必需的。 这些研究是迈向CDI治疗临床研究和/或的关键第一步。 利用PGE2对结肠健康的有益影响的预防。这些成功完成 研究将立即对CDI的新临床研究产生直接影响，可能会提供更多理由使用的证据 高CDI风险患者的NSAID。