Mice deficient in the gene for cytochrome P450 (CYP)1A1 are more susceptible than wild-type to hyperoxic lung injury: evidence for protective role of CYP1A1 against oxidative stress.

Abstract

Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome in adults and bronchopulmonary dysplasia in premature infants. Cytochrome P450 (CYP)1A1 has been shown to modulate hyperoxic lung injury. The mechanistic role(s) of CYP1A1 in hyperoxic lung injury in vivo is not known. In this investigation, we hypothesized that Cyp1a1(-/-) mice would be more susceptible to hyperoxic lung injury than wild-type (WT) mice, and that the protective role of CYP1A1 is in part due to CYP1A1-mediated decrease in the levels of reactive oxygen species-mediated lipid hydroperoxides, e.g., F2-isoprostanes/isofurans, leading to attenuation of oxidative damage. Eight- to ten-week-old male WT (C57BL/6J) or Cyp1a1(-/-) mice were exposed to hyperoxia (>95% O2) or room air for 24-72 h. The Cyp1a1(-/-) mice were more susceptible to oxygen-mediated lung damage and inflammation than WT mice, as evidenced by increased lung weight/body weight ratio, lung injury, neutrophil infiltration, and augmented expression of IL-6. Hyperoxia for 24-48 h induced CYP1A expression at the mRNA, protein, and enzyme levels in liver and lung of WT mice. Pulmonary F2-isoprostane and isofuran levels were elevated in WT mice after hyperoxia for 24 h. On the other hand, Cyp1a1(-/-) mice showed higher levels after 48-72 h of hyperoxia exposure compared to WT mice. Our results support the hypothesis that CYP1A1 protects against hyperoxic lung injury by decreasing oxidative stress. Future research could lead to the development of novel strategies for prevention and/or treatment of acute lung injury.

• Authors: Krithika Lingappan, Weiwu Jiang, Lihua Wang, Gangduo Wang, Xanthi I Couroucli, Binoy Shivanna, Stephen E Welty, Roberto Barrios, M Firoze Khan, Daniel W Nebert, L Jackson Roberts, Bhagavatula Moorthy
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 141 Issue 1 Pg. 68-77 (Sep 2014) ISSN: 1096-0929 [Electronic] United States
• PMID: 24893714 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Cytochrome P-450 CYP1A1

Topics

• Acute Lung Injury (enzymology, genetics, pathology, prevention & control)
• Animals
• Blotting, Western
• Body Weight
• Cytochrome P-450 CYP1A1 (genetics)
• Hyperoxia (enzymology, genetics, pathology)
• Lipid Peroxidation (genetics)
• Lung (enzymology, pathology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Neutrophil Infiltration (genetics)
• Organ Size
• Oxidative Stress (genetics)