Fatal cases of acute
shock complicating Clostridium sordellii
endometritis following medical abortion with
mifepristone (also known as
RU-486) used with
misoprostol were reported. The pathogenesis of this unexpected complication remains enigmatic.
Misoprostol is a pharmacomimetic of
PGE(2), an endogenous suppressor of innate immunity. Clinical C. sordellii
infections were associated with intravaginal
misoprostol administration, suggesting that high
misoprostol concentrations within the uterus impair immune responses against C. sordellii. We modeled C. sordellii
endometritis in rats to test this hypothesis. The intrauterine but not the intragastric delivery of
misoprostol significantly worsened mortality from C. sordellii uterine
infection, and impaired bacterial clearance in vivo.
Misoprostol also reduced
TNF-alpha production within the uterus during
infection. The intrauterine injection of
misoprostol did not enhance mortality from
infection by the vaginal commensal bacterium Lactobacillus crispatus. In vitro,
misoprostol suppressed macrophage
TNF-alpha and
chemokine generation following C. sordellii or
peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordellii, and inhibited uterine epithelial cell human
beta-defensin expression. These immunosuppressive effects of
misoprostol, which were not shared by
mifepristone, correlated with the activation of the G(s)
protein-coupled E
prostanoid (EP) receptors EP2 and EP4 (macrophages) or EP4 alone (uterine epithelial cells). Our data provide a novel explanation for
postabortion sepsis leading to death and also suggest that
PGE(2), in which production is exaggerated within the reproductive tract during pregnancy, might be an important causal determinant in the pathogenesis of more common
infections of the gravid uterus.