Mechanisms of CYP1A regulation and lung injury by oxygen

描述(由申请人提供)：高氧血症通常用于肺功能不全的患者，如早产儿和患有急性呼吸道疾病综合征的成年人。高氧性肺损伤的分子机制尚不清楚。这项研究的中心假设是，在体内和细胞培养系统中，高氧通过转录激活相应启动子的机制诱导细胞色素P1A酶，诱导的细胞色素P1A酶通过催化ROS生成的分子(如F2异前列腺素和异呋喃)的解毒在高氧性肺损伤中发挥保护作用，这些分子的水平在高氧肺中升高。我们提出了两个具体目标。1.验证一种假设，即缺乏CYP1A1、1A2基因或这两种基因的小鼠(CYP1A1/1A2双基因敲除)比类似暴露的野生型小鼠更容易发生高氧性肺损伤。2.研究高氧对小鼠肝、肺细胞CYP1A1基因调控的分子机制。拟议的研究应该有助于开发新的策略来预防/治疗正在接受补充氧疗的人类的肺部疾病。

DESCRIPTION (provided by applicant): Hyperoxia is used routinely in patients suffering from pulmonary insufficiency, as is encountered in preterm infants and in adults with acute respiratory disease syndrome. The molecular mechanisms of lung injury caused by hyperoxia are not known. The central hypothesis of the research proposed here is that hyperoxia induces CYP1A enzymes in vivo and in cell culture systems by mechanisms involving transcriptional activation of the corresponding promoters, and that the induced CYP1A enzymes play protective roles in hyperoxic lung injury by catalyzing the detoxication of ROS-generated molecules (e.g., F2 isoprostanes and isofurans), whose levels are elevated in hyperoxic lungs. We proposed 2 Specific Aims. 1. To test the hypothesis that mice lacking the gene for CYP1A1, 1A2, or both genes (CYP1A1/1A2 double knockouts) will be more susceptible to hyperoxic lung injury than similarly exposed wild type mice. 2. To characterize the molecular mechanisms of modulation of CYP1A1 gene by hyperoxia in cultured mouse liver and lung cells. The proposed studies should aid in the development of novel strategies in the prevention/treatment of lung disease in humans undergoing supplemental oxygen therapy.