Investigation into statins as prevention and treatment of inflammation in pregnancy

摘要 早产仍然是新生儿呼吸系统(呼吸道)短期和长期发病率的主要原因 窘迫综合征、支气管肺发育不良)、中枢神经(脑室内出血、脑室周围 白质软化症、脑瘫)和胃肠系统(坏死性小肠结肠炎)，以及死亡率。 肺结核病谱的主要机制及其相关的不良新生儿结局被夸大了 继发于感染性或非感染性病因的母婴/新生儿炎症 我们的中心假设是，产前应用他汀类药物可以消除胎儿的炎症反应 提高内毒素诱导的小鼠全身性母体组织中血红氧合酶-1的表达 发炎。 提出的假设将在一个已建立的动物模型中进行研究，在该模型中，怀孕的小鼠 使用亲脂性(辛伐他汀)或亲水性(普伐他汀)他汀加和不加HO-1抑制剂治疗 腹膜腔内注射脂多糖前后。 这些研究具有临床意义，因为它们将1)确定性别差异对母亲的反应 炎症和他汀类药物治疗，2)确定HO-1‘S在预防胎儿/新生儿炎症损伤中的作用 他汀类药物，3)确定亲脂性他汀类药物与亲水性他汀类药物在预防胎儿 对母体全身炎症的炎症反应。AIMS的成功测试将带来新的 预防早产胎儿并发症的治疗发展范例。

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.