Mechanisms of CYP1A regulation and lung injury by oxygen

描述（由申请方提供）：高氧通常用于肺功能不全患者，如早产儿和急性呼吸道疾病综合征成人。高氧引起肺损伤的分子机制尚不清楚。本文提出的研究的中心假设是，高氧通过涉及相应启动子的转录激活的机制在体内和细胞培养系统中诱导CYP 1A酶，并且诱导的CYP 1A酶通过催化ROS产生的分子（例如，F2异前列烷和异呋喃），其水平在高氧肺中升高。我们提出了两个具体目标。1.为了检验缺乏CYP 1A 1、1A 2基因或两种基因（CYP 1A 1/1A 2双敲除）的小鼠比类似暴露的野生型小鼠更容易发生高氧肺损伤的假设。2.探讨高氧对小鼠肝、肺细胞CYP 1A 1基因表达的影响及其分子机制。拟议的研究应有助于开发新的策略，在预防/治疗肺部疾病的人接受补充氧气治疗。

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.