Disruption of cytochrome P4501A2 in mice leads to increased susceptibility to hyperoxic lung injury |
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| Affiliation: | 1. Division of Neonatal–Perinatal Medicine, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USA;2. Department of Pathology, Houston Methodist Research Institute, Houston, TX 77030, USA;3. Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA;4. Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;5. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37240, USA;1. Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado;2. Division of Pediatric Surgery, Department of Surgery, University of Colorado School of Medicine, Aurora, Colorado;3. Division of Pediatric Surgery at CCHMC, Department of Surgery, University of Cincinnati, Cincinnati, Ohio;4. Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado;1. Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands;2. Groningen Research Institute for Asthma and COPD, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;3. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;4. Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands;5. Division of Respiratory Medicine, Nottingham University Hospitals, QMC Campus, Nottingham NG7 2UH, United Kingdom;6. Woolcock Institute of Medical Research, Glebe 2037, Australia;7. Discipline of Pharmacology, The University of Sydney, Sydney 2006, Australia;8. Division of Respiratory Medicine, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom;1. Department of Obstetrics and Gynecology, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel;2. Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel;3. Department of Pediatrics, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel;1. Centre for Toxicogenomics and Human Health (ToxOmics), Genetics, Oncology and Human Toxicology, NOVA Medical School/FCM, Universidade Nova de Lisboa, Portugal;2. Université de Toulouse, INSA, UPS, INP, LISBP, 135 Avenue de Rangueil, F-31077 Toulouse, France;3. INSA UMR 792 Ingénierie des Systèmes Biologiques et des Procédés, F-31400 Toulouse, France;4. CNRS UMR5504, 135 Avenue de Rangueil, F-31400 Toulouse, France |
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| Abstract: | Hyperoxia contributes to acute lung injury in diseases such as acute respiratory distress syndrome. Cytochrome P450 (CYP) 1A enzymes have been implicated in hyperoxic lung injury, but the mechanistic role of CYP1A2 in pulmonary injury is not known. We hypothesized that mice lacking the gene Cyp1a2 (which is predominantly expressed in the liver) will be more sensitive to lung injury and inflammation mediated by hyperoxia and that CYP1A2 will play a protective role by attenuating lipid peroxidation and oxidative stress in the lung. Eight- to ten-week-old WT (C57BL/6) or Cyp1a2−/− mice were exposed to hyperoxia (>95% O2) or maintained in room air for 24–72 h. Lung injury was assessed by determining the ratio of lung weight/body weight (LW/BW) and by histology. Extent of inflammation was determined by measuring the number of neutrophils in the lung as well as cytokine expression. The Cyp1a2−/− mice under hyperoxic conditions showed increased LW/BW ratios, lung injury, neutrophil infiltration, and IL-6 and TNF-α levels and augmented lipid peroxidation, as evidenced by increased formation of malondialdehyde– and 4-hydroxynonenal–protein adducts and pulmonary isofurans compared to WT mice. In vitro experiments showed that the F2-isoprostane PGF2-α is metabolized by CYP1A2 to a dinor metabolite, providing evidence for a catalytic role for CYP1A2 in the metabolism of F2-isoprostanes. In summary, our results support the hypothesis that hepatic CYP1A2 plays a critical role in the attenuation of hyperoxic lung injury by decreasing lipid peroxidation and oxidative stress in vivo. |
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| Keywords: | Acute lung injury CYP1A2 ARDS Oxidative stress Free radicals |
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