Mechanisms of CYP1A regulation and lung injury by oxygen

描述（由申请人提供）：高氧常规用于肺功能不全的患者，如早产儿和急性呼吸系统疾病综合征的成人。高氧肺损伤的分子机制尚不清楚。本研究提出的中心假设是，高氧在体内和细胞培养系统中通过相应启动子的转录激活机制诱导CYP1A酶，诱导的CYP1A酶通过催化ros生成的分子（如F2异前列腺素和异脲）的解毒，在高氧肺损伤中发挥保护作用，其水平在高氧肺中升高。我们提出了2个具体目标。为了验证缺乏CYP1A1、1A2基因或两种基因（CYP1A1/1A2双敲除）的小鼠比同样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CYP1A1基因调控的分子机制。拟议的研究应有助于开发新的策略，以预防/治疗人类进行补充氧治疗的肺部疾病。

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.