Investigation into statins as prevention and treatment of inflammation in pregnancy

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ABSTRACT Prematurity remains a leading cause of short- and long-term neonatal morbidity of the respiratory (respiratory distress syndrome, bronchopulmonary dysplasia), central nervous (intraventricular hemorrhage, periventricular leukomalacia, cerebral palsy), and gastrointestinal systems (necrotizing enterocolitis), as well as mortality. Leading mechanisms for the PTB spectrum and its related adverse neonatal outcomes are exaggerated maternal and fetal/neonatal inflammation, secondary to infectious or noninfectious etiologies Our central hypothesis is that prenatal administration of statins abolishes the inflammatory responses in fetal tissues by increasing the hemoxygenase-1 expression in a murine model of LPS-induced systemic maternal inflammation. The proposed hypothesis will be investigated in an established animal model, in which pregnant mice are treated with either a lipophilic (simvastatin) or hydrophilic (pravastatin) statin with and without HO-1 inhibitor before or after intra-peritoneal administration of LPS. These studies are clinically significant as they will 1) determine gender differences in response to maternal inflammation and statin treatment, 2) determine HO-1’s role in preventing fetal/neonatal inflammatory injury by statins, and 3) establish the effectiveness of lipophilic versus hydrophilic statins in preventing fetal inflammatory response to maternal systemic inflammation. Successful testing of aims will introduce new paradigms for development of therapies to prevent fetal complications of preterm birth.