PARTICIPATION OF INFLAMMATORY AGENTS IN A MODEL OF SEPTIC PREGNANCY LOSS INDUCED BY LPS

AISEMBERG JULIETA; VERCELLI, CLAUDIA; BILLI SILVIA; RIBEIRO MARIA LAURA; FRANCHI, ANA MARIA

SAN PABLO, BRASIL

Congreso; XIV CONGRESO DE LA SOCIEDAD BRASILERA DE BIOLOGIA CELULAR; 2008

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US; mso-fareast-language:ES-AR;} @page Section1 {size:612.0pt 792.0pt; margin:45.0pt 3.0cm 70.85pt 99.25pt; mso-header-margin:35.45pt; mso-footer-margin:35.45pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Although there has been some progress in the understanding of the cause of early pregnancy loss due to chromosomal abnormalities, there is a dearth of knowledge of the causes of isolated and recurrent loss in euploid conceptuses. Genital tract bacterial infections could induce abortion and are some of the most common complications of pregnancy; however, the mechanisms remain unclear. In the early pregnancy, low doses of LPS that reproduce most of the systemic and cellular effects of sepsis, without affecting maternal survival, produce high percentage of embryonic resorption (ER).   We investigated the role of several inflammatory agents in the mechanism of LPS-induced pregnancy loss in a mouse model. We have demonstrated that nitric oxide (NO) and prostaglandins (PG) are involved in the ER, observing augmented production of these molecules and that inhibitors of their synthesis could prevent ER. LPS also caused an increase in the oxidative damage, evidenced by nitration of tyrosine proteins, due to the peroxynitrite anion. We have also observed that LPS was able to increase in vitro uterine and decidual synthesis of PGE, NO and TNFa and this effect was abrogated by progesterone (P). The serum levels of this hormone were diminished in the LPS treated animals. The non-rejection of the fetus in normal pregnancies has been attributed to a number of mechanisms, one of which may be the presence of immunomodulatory molecules induced by P within the feto-placental unit. So we characterized the uterine and decidual production of two of these molecules: PP14 (Progestagen-dependent endometrial protein) and LIF (Leukemia inhibitory factor). PP14 is expressed in maternal reproductive tracts and is highly abundant during early pregnancy, and it has anti- inflammatory effects. LIF, a pro-inflammatory cytokine, is one of the molecules known to be indispensable for mouse blastocyst implantation. PP14 protein levels in LPS-treated animals were significantly lower than in control group while LIF mRNA expression was increased. P increased LIF mRNA expression in normal pregnant mice in vitro and it  blocked LIF increase stimulated by  LPS. Anandamide (AEA), the major endocannabinoid studied so far, has a role in implantation and embryo development. However, high levels of this molecule correlate with fetal weight loss and abortion. We evaluated if AEA participates in the mechanism of LPS-induced NO production on early murine pregnancy. LPS treatment augmented uterine AEA synthesis and decreased its degradation. We also observed that antagonists of cannabinoid receptors blocked the augmentation of NO due to LPS suggesting that AEA could have an anti-inflammatory effect. These results suggest that several inflammatory molecules could participate in the mechanism of LPS-induced resorption and that modulation could be useful tools to prevent early pregnancy loss.