Nitric oxide mediates prostaglandins' deleterious effect on lipopolysaccharide-triggered murine fetal resorption

Abstract

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...

Uterine disorders and pregnancy complications: insights from mouse models

“…TLR4 signaling also seems to be involved in regulating PG metabolism, inducing preterm labor in this model (133,134). Overproduction of PGs via COX-2 is noted in the LPS model of preterm birth and is highly associated with increased embryonic resorption in mice (135). Nitric oxide and endocannabinoids are also implicated in LPS-induced tissue damage in the mouse model of preterm birth (136).…”

Neuroimmune-Endocrine Interactions during Early Pregnancy in an Autoimmune Context: Focus on Macrophage Activation

“…Recent evidence derived from a lipopolysaccharide (LPS)-induced embryonic resorption model in BALB/c mice indicates that NO and prostaglandins E 2 , F 2 ␣ and thromboxane A 2 increase in uterus and deciduas with a dual role of NO: at low concentrations necessary for implantation [44] , NO inhibited prostaglandin synthesis, while at high levels it increased COX-2 expression and caused abortions [45] .…”

Spontaneous Pregnancy Loss Mediated by Abnormal Maternal Inflammation in Rats Is Linked to Deficient Uteroplacental Perfusion

“…For this, we used a wellestablished rodent model of inflammation-mediated pregnancy loss, in which rats were injected with LPS to induce a maternal inflammatory response. A variety of studies have identified various proinflammatory molecules and immune cells as essential components of the detrimental cascade that leads to fetal death after maternal LPS administration (7,(21)(22)(23)(24)(25). However, surprisingly little is known about the precise mechanisms that initiate fetal death.…”