REPRODUCTION RESEARCH Lipopolysaccharide-induced murine embryonic resorption involves nitric oxide-mediated inhibition of the NADC-dependent 15-hydroxyprostaglandin dehydrogenase Julieta Aisemberg, Marı ´a V Bariani, Claudia A Vercelli, Manuel L Wolfson and Ana M Franchi Centro de Estudios Farmacolo ´gicos y Bota ´nicos (CEFYBO, CONICET-UBA), Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina Correspondence should be addressed to J Aisemberg, Paraguay 2155, Piso 16, C1121ABG, Buenos Aires, Argentina; Email: jaisemberg@yahoo.com.ar Abstract The initial inactivation of prostaglandins (PGs) is mediated by 15-hydroxyprostaglandin dehydrogenase (15-PGDH). PGs are potent mediators of several biological processes, including inflammation and reproduction. In uterus, PGs play a key role in infection- induced pregnancy loss, in which concentration of this mediator increased. This process is accompanied with the induction of nitric oxide synthase expression and a marked increase in uterine levels of nitric oxide. There is no information concerning nitric oxide contribution to potential changes in PG catabolism, but experimental evidence suggests that nitric oxide modulates PG pathways. The specific objectives of the study were to evaluate the protein expression of HPGD (15-PGDH) and to characterize the nitric oxide-dependent regulation of this enzyme in a model of lipopolysaccharide (LPS)-induced embryonic resorption. Results show that LPS decreased HPGD protein expression and augmented PGE synthase activity; therefore, PGE 2 levels increased in uterus in this inflammatory condition. Just as LPS, the treatment with a nitric oxide donor diminished HPGD protein expression in uterine tissue. In contrast, the inhibition of nitric oxide synthesis both in control and in LPS-treated mice increased 15-PGDH levels. Also, we have found that this enzyme and PGE 2 levels are not modulated by peroxynitrite, an oxidant agent derived from nitric oxide. This study suggests that LPS and nitric oxide promote a decrease in the ability of the uterus for PG catabolism during bacterially triggered pregnancy loss in mice. Reproduction (2012) 144 447–454 Introduction Microbial infections are known to cause miscarriage and preterm labor (Romero et al. 1988, Lamont & Sawant 2005) but their mechanisms are still not fully elucidated. Lipopolysaccharide (LPS), a major cell wall component of gram-negative bacteria, induces activation of immune cells. Activated macrophages produce several inflam- matory cytokines including tumor necrosis factor a, interleukin 6 and 12, which, when in excess, leads to the onset of reproductive disorders or diseases (Penta et al. 2003). We have previously developed a mouse model to study the mechanisms of LPS-induced pregnancy loss. The administration of 1 mg/g of body weight (i.p.) of LPS in mice on day 7 of pregnancy produced complete embryonic resorption at 24 h. We have observed that the decidua, which envelops the embryo, was necrotized 24 h after LPS injection and this resorbed tissue was expelled the following day. In this model, nitric oxide and prostaglandins (PGs) are highly produced in implantation sites of mouse uterus during the infection/ inflammation-induced embryonic resorption process (Ogando et al. 2003, Aisemberg et al. 2007). PG biosynthesis is catalyzed by cyclooxygenase 1 and 2 enzymes (Rouzer & Marnett 2009) and the first step of its inactivation is due to the NADC-dependent 15-hydroxyprostaglandin dehydrogenase that catalyzes the conversion of primary PGs to their biologically inactive 15-keto derivatives (Tai et al. 2006). The products, 15-keto metabolites, exhibit greatly reduced biological activities rendering this enzyme being a key enzyme responsible for the biological inactivation of these eicosanoids. A tight control over PG metabolism is critical for the maintenance of pregnancy, in part because they act as potent uterotonins affecting myo- metrial contractility. During early gestation, HPGD (15-PGDH) activity has been shown to increase (Keirse et al. 1985), and for most of the duration of pregnancy, 15-PGDH minimizes myometrial contractility, keeping PGs synthesized by amnion or chorion (Sangha et al. 1994). Therefore, changes in HPGD protein levels or q 2012 Society for Reproduction and Fertility DOI: 10.1530/REP-12-0186 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via www.reproduction-online.org Downloaded from Bioscientifica.com at 10/14/2021 12:46:15AM via free access