Investigation into statins as prevention and treatment of inflammation in pregnancy

他汀类药物预防和治疗妊娠期炎症的研究

• 批准号: 9975203
• 负责人: Egle Bytautiene Prewit
• 金额: $ 8.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9975203
• 关键词: Accounting; Alveolar; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Birth; Brain; Bronchopulmonary Dysplasia; CASP3 gene; Cerebral Palsy; Coenzyme A; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotides; Effectiveness; Encephalitis; Epidemiology; Etiology; Exposure to; Female; Fetal Tissues; Gastrointestinal tract structure; Gene Expression; Genetic Transcription; Goals; Goblet Cells; IL8 gene; Incubated; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Interleukin-1 beta; Interleukin-10; Interleukin-4; Interleukin-6; Intestines; Investigation; Lipopolysaccharides; Lung; MAP Kinase Gene; MAPK8 gene; Measures; Mediating; Microtubules; Mitogens; Modeling; Mus; Myelin Basic Proteins; Necrotizing Enterocolitis; Neonatal; Neonatal respiratory morbidity; Neuraxis; Neurologic; Outcome; Oxidoreductase; Paneth Cells; Pathway interactions; Periventricular Leukomalacia; Phosphotransferases; Pravastatin; Pregnancy; Premature Birth; Premature Labor; Prevention; Property; Protein Kinase C; Proteins; Regulation; Reporting; Rho-associated kinase; Role; Secondary to; Simvastatin; Soluble Guanylate Cyclase; TNF gene; Testing; Therapeutic; Tissues; Transcription Factor AP-1; Up-Regulation; Vascular Endothelial Growth Factors; body system; clinically significant; congenital anomaly; cytokine; design; experimental study; farnesyl pyrophosphate; fetal; fetal brain injury; gastrointestinal system; gender difference; geranylgeranyl pyrophosphate; hydrophilicity; infant death; inflammatory marker; inhibitor/antagonist; intraperitoneal; intraventricular hemorrhage; lipophilicity; male; mortality; mouse model; neonatal outcome; p38 Mitogen Activated Protein Kinase; phosphoric diester hydrolase; pregnant; premature; prenatal; preterm premature rupture of membranes; prevent; primary outcome; protein kinase inhibitor; pup; respiratory distress syndrome; response; secondary outcome; therapy development; transcription factor

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.

摘要 早产仍然是新生儿呼吸系统（呼吸道）短期和长期发病的主要原因。 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 脑白质软化、脑性麻痹）和胃肠道系统（坏死性小肠结肠炎）以及死亡率。 PTB谱及其相关不良新生儿结局的主要机制被夸大 继发于感染性或非感染性病因的母体和胎儿/新生儿炎症 我们的中心假设是，产前给予他汀类药物消除了胎儿的炎症反应， 通过增加LPS诱导的系统性母体妊娠小鼠模型中血红素加氧酶-1的表达， 炎症 将在已建立的动物模型中研究所提出的假设，在该模型中， 用亲脂性（辛伐他汀）或亲水性（普伐他汀）他汀类药物治疗，伴或不伴HO-1抑制剂 在腹膜内施用LPS之前或之后。 这些研究具有临床意义，因为它们将：1）确定对孕产妇死亡反应的性别差异 炎症和他汀类药物治疗，2）确定HO-1在预防胎儿/新生儿炎性损伤中的作用， 他汀类药物，和3）建立亲脂性与亲水性他汀类药物在预防胎儿 对母体全身性炎症的炎症反应。AIMS的成功测试将引入新的 预防早产胎儿并发症的治疗方法的发展范例。