Role of misoprostol in Clostridium sordellii endometritis in a rodent model

米索前列醇在啮齿动物模型中索氏梭菌子宫内膜炎中的作用

• 批准号: 8277067
• 负责人: David M Aronoff
• 金额: $ 31.15万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277067
• 关键词: Acute; Address; Adverse effects; Agonist; Anaerobic Bacteria; Anti-Progestin; Arachidonic Acids; Area; Bacteria; Binding; Cell membrane; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clostridium; Clostridium Infections; Clostridium sordellii; Coupled; Cyclic AMP; Cytosolic Phospholipase A2; Data; Development; Dinoprostone; Disease; Dose; EP4 receptor; Educational workshop; Emerging Communicable Diseases; Endometritis; Enzymes; Epithelial Cells; FDA approved; Female; Fostering; Foundations; GTP-Binding Proteins; Generations; Host Defense; Human; Immune; Immune system; Immunity; Immunology; Immunosuppression; In Vitro; Induced Abortion; Infection; Inflammation Mediators; Investigation; Joints; Knowledge; Label; Laboratories; Leukocytes; Medical; Medicine; Membrane; Methods; Mifepristone; Misoprostol; Myometrial; Natural Immunity; Nature; Oral; Oral cavity; Pathogenesis; Phagocytosis; Pharmaceutical Preparations; Pregnancy; Production; Prostaglandin H2; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Public Health; Qualifying; RU-486; Receptor Signaling; Regimen; Reporting; Reproductive Tract Infections; Research; Risk; Rodent Model; Role; Safety; Sepsis Syndrome; Signal Transduction; Synthetic Prostaglandins; Termination of pregnancy; Testing; Time; Tissues; United States National Institutes of Health; Uterine Contraction; Uterus; Vagina; Woman; Women' s Health; abortion; analog; cyclooxygenase 1; human WFDC2 protein; immunoregulation; in vivo; innate immune function; insight; killings; lipid mediator; macrophage; meetings; microbiome; mouse PGE synthase 1; neutrophil; novel; pathogen; prostaglandin EP2 receptor; prostaglandin EP3 receptor; prostanoid receptor EP1; public health relevance; receptor; receptor coupling; reproductive; research study

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.

描述（由申请人提供）：米非司酮（MFP;也称为RU-486）和米索前列醇的组合口服方案于2000年被FDA批准用于药物流产。然而，米索前列醇通常用于阴道内（标签外），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，出现了由梭菌引起的子宫感染（并死于）。口服米索前列醇时未报告类似病例。这些死亡的戏剧性性质促使FDA，NIH和CDC在2006年5月举行了一次新兴梭菌病研讨会，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（PGE 2）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。PGE 2通过其增加白细胞和结构细胞中细胞内cAMP浓度的能力，有效地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的可能性似乎没有得到考虑。这一提议提出了新的假设，即高局部浓度的米索前列醇抑制女性生殖道内的免疫系统，并促进C。梭菌感染这些作用可能是剂量依赖性的，当米索前列醇阴道内给药时，局部子宫组织浓度最高。我们将采用体外和体内实验来验证这一假设。本提案的具体目的是（1）描述米索前列醇和MFP对C. sordellii和人蜕膜巨噬细胞和血液中性粒细胞;（2）确定米索前列醇和MFP对人子宫上皮细胞在C. sordellii感染;（3）确定米索前列醇和MFP治疗对阴道定植和C. Sordellii acrylattis in vivo.这些研究将提供新的信息，可能允许更安全的药物流产方法。他们还将首次描述C之间的相互作用。Sordellii和女性生殖道之间以及前列腺素类和女性生殖道之间的关系-特别相关，因为怀孕本身就是一种高内源性PGE 2的状态。我们的实验室是唯一有资格进行这些研究，并探讨米索前列醇和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研究不足的医学领域获得新的科学知识：妇女健康，堕胎安全，女性生殖道免疫学，微生物组，C。Sordellii发病机制和PGE 2的免疫调节作用。公共卫生关系：这项研究与公共卫生的相关性：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，几名健康妇女死于由梭菌引起的罕见宫内感染，发生在妊娠终止后几天。每例死亡均与阴道内超说明书使用双倍剂量米索前列醇（一种具有强效免疫抑制作用的合成前列腺素类似物）有关。研究米索前列醇通过抑制女性生殖道免疫力促进梭菌感染的新假设将促进更安全的堕胎药物的开发，增加对妊娠期间女性生殖道免疫系统的了解，并提供有关天然和合成艾美兰素免疫调节作用的更深入了解。

项目成果

Cyclooxygenase inhibition in sepsis: is there life after death?

• DOI: 10.1155/2012/696897
• 发表时间: 2012
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Aronoff DM

Comparative analysis of the extracellular proteomes of two Clostridium sordellii strains exhibiting contrasting virulence.

对表现出不同毒力的两种索氏梭菌菌株的细胞外蛋白质组进行比较分析。

• DOI: 10.1016/j.anaerobe.2010.03.004
• 发表时间: 2010
• 期刊: Anaerobe
• 影响因子: 2.3
• 作者: Kachman,MaureenT;Hurley,MaryC;Thiele,Teri;Srinivas,Geetha;Aronoff,DavidM
• 通讯作者: Aronoff,DavidM

Postpartum group a Streptococcus sepsis and maternal immunology.

• DOI: 10.1111/j.1600-0897.2011.01083.x
• 发表时间: 2012-02
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)
• 作者: Mason KL;Aronoff DM
• 通讯作者: Aronoff DM

EP4 and EP2 receptor activation of protein kinase A by prostaglandin E2 impairs macrophage phagocytosis of Clostridium sordellii.

• DOI: 10.1111/aji.12153
• 发表时间: 2014-01
• 期刊: American journal of reproductive immunology (New York, N.Y. : 1989)
• 作者: Rogers LM;Thelen T;Fordyce K;Bourdonnay E;Lewis C;Yu H;Zhang J;Xie J;Serezani CH;Peters-Golden M;Aronoff DM
• 通讯作者: Aronoff DM