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.
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 wild-type 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.
Jiang
Weiwu
W
Department of Pediatrics, Baylor College of Medicine, 6621 Fannin, FC 530.01, Houston, TX 77030, USA. . bmoorthy@bcm.tmc.edu
Welty
Stephen E
SE
Couroucli
Xanthi I
XI
Barrios
Roberto
R
Kondraganti
Sudha R
SR
Muthiah
Kathirvel
K
Yu
Ling
L
Avery
Stephen E
SE
Moorthy
Bhagavatula
B
D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010100:Oxygen / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*
D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D010100:Oxygen