Regulation of pulmonary and hepatic cytochrome P4501A expression in the rat by hyperoxia: Implications for hyperoxic lung injury
Regulation of pulmonary and hepatic cytochrome P4501A expression in the rat by hyperoxia: Implications for hyperoxic lung injury
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DOI：
10.1124/mol.61.3.507
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发表时间：
2002-03-01
影响因子：
3.6
通讯作者：
Moorthy, B
中科院分区：
文献类型：
--
作者：
Couroucli, XI;Welty, SE;Moorthy, B
补充氧气治疗常用于治疗肺功能不全，如早产儿和急性呼吸窘迫综合征患者。然而，高氧会导致实验动物的肺损伤，也可能会导致人类的肺损伤。细胞色素P4501 A酶与高氧肺损伤有关。在这项研究中，我们研究了高氧对CYP 1A 1调节的机制，并验证了芳烃受体（AHR）依赖性机制有助于诱导CYP 1A 1和高氧对CYP 1A的调节可能对肺损伤有影响的假设。成年雄性Sprague-Dawley大鼠暴露于高氧24至48 h导致肺CYP 1A 1酶表达增加，之前是相应mRNA的增强，随后在60 h时诱导下降，此时动物表现出严重的呼吸窘迫和肺部炎症。类似地，在高氧24 - 48 h之间，肝脏CYP 1A 1/1A 2 mRNAs被显著诱导，60 h时诱导作用下降。电泳迁移率变动分析（EMSA）和AHR（-/-）小鼠实验表明，AHR依赖性机制有助于CYP 1A诱导。AHR（-/-）小鼠对高氧诱导的CYP 1A 1不敏感，对肺损伤比野生型小鼠更敏感。高氧组大鼠肺组织中，气道上皮细胞、II型肺上皮细胞和内皮细胞中CYP 1A 1表达增加。总之，我们的研究结果表明，高氧诱导CYP 1A 1是介导的AHR依赖性机制和高氧的CYP 1A酶的调制可能有影响高氧肺损伤。
Supplemental oxygen therapy is frequently used in the treatment of pulmonary insufficiency, as is encountered in premature infants, and in patients with acute respiratory distress syndrome. However, hyperoxia causes lung damage in experimental animals and may do so in humans. Cytochrome P4501A enzymes have been implicated in hyperoxic lung injury. In this study, we investigated the mechanisms of CYP1A1 regulation by hyperoxia and tested the hypothesis that aryl hydrocarbon receptor (AHR)-dependent mechanisms contribute to induction of CYP1A1 and that modulation of CYP1A by hyperoxia may have implications for lung injury. Exposure of adult male Sprague-Dawley rats to hyperoxia for 24 to 48 h led to increased expression of pulmonary CYP1A1 enzyme, which was preceded by enhancement of the corresponding mRNA, followed by decline of induction at 60 h, when the animals displayed severe respiratory distress and lung inflammation. Similarly, hepatic CYP1A1/1A2 mRNAs were markedly induced between 24 and 48 h of hyperoxia, with induction declining by 60 h. Electrophoretic mobility shift assays (EMSA) and experiments with AHR (-/-) mice indicated that AHR-dependent mechanisms contributed to CYP1A induction. The AHR (-/-) mice were refractory to CYP1A1 induction by hyperoxia and were more sensitive to lung injury than wild-type mice. Lungs of hyperoxic rats showed increase in the expression of CYP1A1 in airway epithelial cells, type II pneumocytes, and endothelial cells. In conclusion, our results suggest that induction of CYP1A1 by hyperoxia is mediated by AHR-dependent mechanisms and that modulation of CYP1A enzymes by hyperoxia may have implications for hyperoxic lung injury.