Submitted on August 14, 2003
Accepted on January 29, 2004
Excess Nitric Oxide Decreases Cytochrome P450 2J4 (CYP2J4) Content and P450-Dependent Arachidonic Acid Metabolism in Lung of Rats with Acute Pneumonia
Asma Yaghi1, John R. Bend2, Christopher D. Webb2, Darryl C. Zeldin3, Sean Weicker4, Sanjay Mehta4, and David G. McCormack4*
1 Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; Respirology, London Health Sciences Centre, Victoria Campus, AC burton Vascular Biology Laboratory, Lawson Health Research Institute, London, Ontario, Canada
2 Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
3 NIH, National Institute of Environmental Health Sciences, Research Triangle Park, N.C., USA
4 Respirology, London Health Sciences Centre, Victoria Campus, AC burton Vascular Biology Laboratory, Lawson Health Research Institute, London, Ontario, Canada; Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada
* To whom correspondence should be addressed. E-mail: david.mccormack{at}lhsc.on.ca.
Recently, we demonstrated that pulmonary CYP2J4 content, a prominent source of EETs and HETEs formation in rat lungs, is reduced in pneumonia. Therefore, the purpose of this study was to determine the role of iNOS-derived NO in reduced pulmonary CYP2J4 protein content and decreased CYP metabolites in pneumonia. Rats were randomized to control, control+1400W (iNOS inhibitor), pneumonia and pneumonia+1400W groups. Pseudomonas organisms were
injected into the lungs of pneumonia rats. At 40 hr after surgery rats were treated with either saline or 1400W for 4 hr before sacrifice. Venous plasma samples were obtained for measuring nitrites/nitrates (NOX). There was no significant effect of 1400W on blood pressure measured in
control or pneumonia rats, whereas 1400W reduced the elevated plasma NOX levels in pneumonia rats by half. CYP primary metabolites of AA were formed at significantly lower rates in pulmonary microsomes from pneumonia rats compared to control rats. Treatment of pneumonia rats with 1400W resulted in a significant increase in the rate of formation of pulmonary EETs and omega-terminal HETEs compared to untreated pneumonia rats. The reduction in CYP2J4 protein content in pneumonia lung microsomes was also partially prevented by 1400W. Therefore, excess NO from iNOS decreases the pulmonary production of EETs and omega HETEs in acute pneumonia. Inhibition of iNOS restores CYP2J4 protein content and CYP activity in acute pneumonia, indicating an important NO-CYP interaction in pulmonary responses to infection. We speculate that CYP2J4 and its AA metabolites are involved in the modulation of pulmonary function in health and disease.
