Role of misoprostol in Clostridium sordellii endometritis in a rodent model

描述（由申请人提供）：米非司酮（MFP；也称为RU-486）和米索前列醇联合口服方案于2000年被FDA批准用于医学人工流产。然而，米索前列醇通常用于阴道内（未标示），以增加成功流产的可能性并减少全身不良反应。从2001年开始，几名原本健康的妇女在使用口服MFP/阴道米索前列醇方案的几天内，出现了由梭氏梭状芽胞杆菌引起的严重子宫感染（并死于这种感染）。口服米索前列醇未见类似病例的报道。这些死亡的戏剧性促使FDA、NIH和CDC在2006年5月举行了一个新兴梭状菌病研讨会，呼吁对这一主题进行更多的研究。米索前列醇是前列腺素E2 （PGE2）的合成类似物，前列腺素E2是一种调节许多正常细胞功能的脂质介质。PGE2通过增加白细胞和结构细胞内cAMP浓度的能力，有效抑制对细菌病原体的免疫防御，我们的初步数据表明米索前列醇也具有这些作用。值得注意的是，米索前列醇的免疫抑制作用可能是这种新出现的传染病的一个因素，这一可能性似乎没有得到考虑。这一建议解决了一个新的假设，即高浓度的米索前列醇抑制了女性生殖道内的免疫系统，并促进了索德利梭菌感染的发展。这些影响可能是剂量依赖性的，当米索前列醇经阴道给药时，局部子宫组织浓度达到最高。我们将采用体外和体内实验来验证这一假设。该提案的具体目的是寻求(1)表征米索前列醇和MFP对梭氏梭氏梭菌与人蜕膜巨噬细胞和血液中性粒细胞相互作用的影响；(2)确定米索前列醇和MFP对梭氏梭菌感染情况下人子宫上皮细胞的影响；(3)确定米索前列醇和MFP治疗对阴道定植和梭氏梭菌子宫内膜炎的体内影响。这些研究将提供新的信息，可能允许采用更安全的药物流产方法。他们还将首次描述梭氏梭状芽胞杆菌与女性生殖道之间以及前列腺素与女性生殖道之间的相互作用，这尤其相关，因为怀孕本身就是一种内源性PGE2高的状态。我们的实验室是唯一有资格进行这些研究，并探索米索前列醇和MFP对细菌-宿主相互作用的抑制作用。这些研究将在几个关键但尚未得到充分研究的医学领域获得新的科学知识：妇女健康、流产安全、女性生殖道免疫学、微生物组、梭氏梭菌发病机制和PGE2的免疫调节。公共卫生相关性：本研究与公共卫生的相关性：在口服米非司酮和口服米索前列醇的药物流产方案于2000年获得FDA批准后，几名健康妇女在妊娠终止后数天死于一种罕见的梭氏梭状芽孢杆菌引起的宫内感染。每次死亡都与超说明书阴道内使用双剂量米索前列醇有关，米索前列醇是一种具有有效免疫抑制作用的合成前列腺素类似物。研究米索前列醇通过抑制女性生殖道免疫促进梭状芽胞杆菌感染的新假设，将促进更安全流产药物的开发，增加对怀孕期间女性生殖道免疫系统的了解，并对天然和合成前列腺素的免疫调节作用提供更深入的了解。

DESCRIPTION (provided by applicant): The combination oral regimen of mifepristone (MFP; also known as RU-486) and misoprostol was FDA approved in 2000 to induce abortion medically. However, misoprostol has commonly been applied intravaginally (off label) to increase the likelihood of successful abortion and reduce systemic adverse effects. Beginning in 2001, several otherwise healthy women developed (and died from) overwhelming infections of the uterus caused by the bacterium Clostridium sordellii, within days of using the oral MFP/vaginal misoprostol regimen. Similar cases have not been reported when misoprostol was administered by mouth. The dramatic nature of these deaths prompted the FDA, NIH, and CDC to hold an Emerging Clostridial Disease Workshop in May, 2006, calling for more research on this subject. Misoprostol is a synthetic analog of prostaglandin E2 (PGE2), a lipid mediator that regulates many normal cellular functions. PGE2 potently suppresses immune defenses against bacterial pathogens through its ability to increase intracellular cAMP concentrations in both leukocytes and structural cells and our preliminary data indicate that misoprostol shares these actions. Remarkably, the possibility that immunosuppressive effects of misoprostol might be a factor in this emerging infectious disease seems not to have received consideration. This proposal addresses the novel hypothesis that high local concentrations of misoprostol suppress the immune system within the female reproductive tract and facilitate the development of C. sordellii infection. These effects are likely dose-dependent, with the highest local uterine tissue concentrations achieved when misoprostol is administered intravaginally. We will employ both in vitro and in vivo experiments to test this hypothesis. The specific aims of this proposal seek to (1) characterize the influence of misoprostol and MFP on interactions between C. sordellii and human decidual macrophages and blood neutrophils; (2) define effects of misoprostol and MFP on human uterine epithelial cells in the context of C. sordellii infection; and (3) determine the impact of misoprostol and MFP treatment on vaginal colonization and C. sordellii endometritis in vivo. These studies will provide new information which may permit safer methods for medical abortion. They will also, for the first time, characterize interactions between C. sordellii and the female reproductive tract and between prostanoids and the female reproductive tract - particularly relevant since pregnancy itself is a state of high endogenous PGE2. Our laboratory is uniquely qualified to conduct these studies, and to explore inhibitory effects of misoprostol and MFP on bacterial-host interactions. These studies will reap new scientific knowledge in several key, yet understudied areas of medicine: women's health, abortion safety, female reproductive tract immunology, the microbiome, C. sordellii pathogenesis, and immunoregulation by PGE2. PUBLIC HEALTH RELEVANCE: Relevance of this research to public health: After the medical abortion regimen of oral mifepristone and oral misoprostol was FDA approved in 2000 several healthy women have died from a rare intrauterine infection caused by Clostridium sordellii, occurring days after pregnancy termination. Each death was associated with the off-label intravaginal use of a double-dose of misoprostol, a synthetic prostaglandin analog with potent immunosuppressive effects. Investigating the novel hypothesis that misoprostol facilitates clostridial infection by inhibiting female reproductive tract immunity will foster the development of safer abortion medications, result in an increased understanding of the female reproductive tract immune system during pregnancy, and provide greater insight regarding the immunomodulatory actions of natural and synthetic prostaglandins.