Disruption of the Ah receptor gene alters the susceptibility of mice to oxygen-mediated regulation of pulmonary and hepatic cytochromes P4501A expression and exacerbates hyperoxic lung injury
Disruption of the Ah receptor gene alters the susceptibility of mice to oxygen-mediated regulation of pulmonary and hepatic cytochromes P4501A expression and exacerbates hyperoxic lung injury
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DOI：
10.1124/jpet.103.059766
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发表时间：
2004-08-01
影响因子：
3.5
通讯作者：
Moorthy, B
中科院分区：
文献类型：
--
作者：
Jiang, WW;Welty, SE;Moorthy, B
在患有肺功能不全的婴儿和患有急性呼吸窘迫综合征的成人中，经常遇到补充氧气的管理。然而，在实验动物中，高氧可引起急性肺损伤。在本研究中，我们研究了Ah受体（AHR）在细胞色素P4501A （CYP1A）酶的调节和高氧肺损伤发展中的作用。将成年雄性野生型[AHR(+/+)]小鼠和AHR（-/-）缺失动物[AHR(-/-)]置于室内空气或高氧（>95%氧气）环境中维持24 ~ 72 h，研究CYP1A在肺和肝脏的表达及肺损伤情况。高氧导致野生型（C57BL/6J） AHR（+/+）小鼠肺和肝脏CYP1A1活性（乙氧基间苯二酚o -去乙基化酶）和mRNA水平显著升高，但AHR（-/-）小鼠无显著升高，提示AHR依赖机制促进了CYP1A1的诱导。另一方面，高氧增强了野生型和AHR（-/-）动物肝脏CYP1A2的表达，表明高氧对CYP1A2的调节机制与AHR无关。暴露于高氧环境下的AHR（-/-）小鼠比野生型小鼠更容易受到肺损伤和炎症的影响，这表明肺重量/体重比明显增加，肺水肿增加，中性粒细胞向肺部募集增加。总之，我们的研究结果支持高氧诱导CYP1A1而非CYP1A2通过AHR依赖机制在体内表达的假设，这一现象可能在机制上有助于AHR在高氧肺损伤中的有益作用。
Administration of supplemental oxygen is frequently encountered in infants suffering from pulmonary insufficiency and in adults with acute respiratory distress syndrome. However, hyperoxia causes acute lung damage in experimental animals. In the present study, we investigated the roles of the Ah receptor (AHR) in the modulation of cytochrome P4501A (CYP1A) enzymes and in the development of lung injury by hyperoxia. Adult male wild-type [AHR (+/+)] mice and AHR-deficient animals [AHR (-/-)] were maintained in room air or exposed to hyperoxia (>95% oxygen) for 24 to 72 h, and pulmonary and hepatic expression of CYP1A and lung injury were studied. Hyperoxia caused significant increases in pulmonary and hepatic CYP1A1 activities ( ethoxyresorufin O-deethylase) and mRNA levels in wild-type (C57BL/6J) AHR (+/+), but not AHR (-/-) mice, suggesting that AHR-dependent mechanisms contributed to CYP1A1 induction. On the other hand, hyperoxia augmented hepatic CYP1A2 expression in both wild-type and AHR (-/-) animals, suggesting that AHR-independent mechanisms contributed to the CYP1A2 regulation by hyperoxia. AHR (-/-) mice exposed to hyperoxia were more susceptible than wildtype mice to lung injury and inflammation, as indicated by significantly higher lung weight/body weight ratios, increased pulmonary edema, and enhanced neutrophil recruitment into the lungs. In conclusion, our results support the hypothesis that the hyperoxia induces CYP1A1, but not CYP1A2, expression in vivo by AHR-dependent mechanisms, a phenomenon that may mechanistically contribute to the beneficial effects of the AHR in hyperoxic lung injury.