Abstract
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.
Footnotes
-
This work was supported in part by a Career Investigator Award CL-005-N from the American Lung Association and Grants R01 ES09132 and R01 HL070921 from the National Institute of Environmental Health Sciences and National Heart, Lung, and Blood Institute, respectively to B.M., and National Heart, Lung, and Blood Institute Grant K08 HL04333 to X.I.C.
-
DOI: 10.1124/jpet.103.059766.
-
ABBREVIATIONS: ROS, reactive oxygen species; P450, cytochrome P450; AHR, Ah receptor; PAH, polycyclic aromatic hydrocarbon; MC, 3-methylcholanthrene; ABT, 1-aminobenzotriazole; EROD, ethoxyresorufin O-deethylase; MROD, methoxyresorufin O-demethylase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ANOVA, analysis of variance; AHREs, Ah response elements; RT-PCR, reverse transcriptase-polymerase chain reaction; Nrf-2, nuclear transcription factor-E2; IL-1β, interleukin 1β.
- Received September 9, 2003.
- Accepted April 29, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|