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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD057176-05
Application #
8277067
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Ilekis, John V
Project Start
2008-09-01
Project End
2013-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$311,519
Indirect Cost
$109,559
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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