Excess nitric oxide decreases cytochrome P-450 2J4 content and P-450-dependent arachidonic acid metabolism in lungs of rats with acute pneumonia.
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 plus 1400W (iNOS inhibitor), pneumonia, and pneumonia plus 1400W groups. Pseudomonas organisms were injected into lungs of pneumonia rats. At 40 h after surgery, rats were treated with either saline or 1400W for 4 h before death. 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 formed at significantly lower rates in pulmonary microsomes from pneumonia rats compared with 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 with 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 CYP2J4 and its AA metabolites are involved in the modulation of pulmonary function in health and disease.
Yaghi
Asma
A
London Health Sciences Research Institute, AC Burton Vascular Biology Laboratory, London Health Sciences Centre, Victoria Campus, 375 South St., London, Ontario, Canada N6A 4G5.
Bend
John R
JR
Webb
Christopher D
CD
Zeldin
Darryl C
DC
Weicker
Sean
S
Mehta
Sanjay
S
McCormack
David G
DG
D000208:Acute Disease; D000578:Amidines / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001596:Benzylamines / Q000494:pharmacology; D001794:Blood Pressure; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D011014:Pneumonia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009566:Nitrates; D009573:Nitrites; D016718:Arachidonic Acid; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C112496:Cyp2j4 protein, rat; D000072467:Cytochrome P450 Family 2