Genital tract bacterial infections could induce abortion and are some of the most common complications of pregnancy; however, the mechanisms remain unclear. We investigated the role of prostaglandins (PGs) in the mechanism of bacterial lipopolysaccharide (LPS)-induced pregnancy loss in a mouse model, and we hypothesized that PGs might play a central role in this action. LPS increased PG production in the uterus and decidua from early pregnant mice and stimulated cyclooxygenase (COX)-II mRNA and protein expression in the decidua but not in the uterus. We also observed that COX inhibitors prevented embryonic resorption (ER). To study the possible interaction between nitric oxide (NO) and PGs, we administered aminoguanidine, an inducible NO synthase inhibitor. NO inhibited basal PGE and PGF 2␣ production in the decidua but activated their uterine synthesis and COX-II mRNA expression under septic conditions. A NO donor (S-nitroso-N-acetylpenicillamine) produced 100% ER and increased PG levels in the uterus and decidua. LPS-stimulated protein nitration was higher in the uterus than in the decidua. Quercetin, a peroxynitrite scavenger, did not reverse LPS-induced ER. Our results suggest that in a model of septic abortion characterized by increased PG levels, NO might nitrate and thus inhibit COX catalytic activity. ER prevention by COX inhibitors adds a possible clinical application to early pregnancy complications due to infections. embryonic resorption ͉ uteri ͉ decidua ͉ peroxynitrite ͉ sepsis M aternal infections could cause abortion in humans (1, 2), but their mechanism is not clear. Spontaneous and cytokineboosted abortion rates have been linked to exposure to lipopolysaccharide (LPS) in the environment (3). Bacteria could enter the uterus with ejaculate or by intestinal absorption (4). Previously, we developed a mouse model to study LPS-induced pregnancy loss (5). LPS (1 g/g i.p.) injected on day 7 of pregnancy produced 100% embryonic resorption (ER) at 24 h, with fetal expulsion at 48 h. Nitric oxide (NO) produced by inducible NO synthase (iNOS) plays a key role in ER (5). LPS produced systemic effects but did not affect the mothers' survival or future pregnancies.Prostaglandin (PG) biosynthesis is catalyzed by cyclooxygenase (COX) I and II, the later being inducible by proinflammatory agents such as cytokines and LPS (6-8). It is well known that PGs mediate septicemic signs and symptoms of Gram-negative bacterial infections and stimulate contractility of the myometrium (9, 10). Thus, PGs are considered to be effective abortifacients and are important mediators of LPS-induced ER and preterm labor. Silver et al. (11) showed that deciduae from LPS-treated mice produce inflammatory eicosanoids as PGE 2 , PGF 2␣ , and thromboxane B 2 and that indomethacin (Indo), a nonselective COX inhibitor, prevents abortion.A significant body of experimental evidence suggests a relationship between NO and PGs (12, 13), particularly in pathophysiologic events associated with gestation. In our laboratory we found that epidermal...
In women, the association between chronic marijuana smoking and early miscarriage has long been known. Anandamide, a major endocannabinoid, mimics some of the psychotropic, hypnotic and analgesic effects of Delta(9)-tetrahydrocannabinol, the psychoactive component of marijuana. The uterus contains the highest concentrations of anandamide yet discovered in mammalian tissues and this suggests that it might play a role in reproduction. The production of small amounts of nitric oxide (NO) regulates various physiological events including implantation and myometrial relaxation, but in an inflammatory setting such as sepsis, NO has toxic effects as it is a free radical. The results presented in this study indicate that anandamide modulates NO production induced by lipopolysaccharide (LPS) in an in-vitro murine model. It was shown that LPS-induced NO synthesis and tissue damage were mediated by anandamide, as a cannabinoid receptor type I antagonist could block the effect of LPS (P < 0.001). This endotoxin inhibited anandamide uterine degradation (P < 0.05) and increased the expression of one of its synthesizing enzymes (P < 0.05). Contrary to the known anti-inflammatory and protective effects, in this model anandamide seems to act as a pro-inflammatory molecule modulating the production of NO induced by LPS. This proinflammatory effect of anandamide may be implicated in pathological reproductive events such as septic abortion.
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