Ketamine-induced hepatoprotection: the role of heme oxygenase-1.
Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 micromol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-kappaB and PPAR-gamma analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-gamma activity, it enhanced NF-kappaB activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.
Suliburk
James W
JW
UT-Houston Medical School, Dept. of Surgery, 6431 Fannin, MSB Suite 4.264, Houston, TX 77030, USA.
Ward
Jeremy L
JL
Helmer
Kenneth S
KS
Adams
Sasha D
SD
Zuckerbraun
Brian S
BS
Mercer
David W
DW
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D002248:Carbon Monoxide / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000502:physiology*; D007649:Ketamine / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D008665:Metalloporphyrins; D016328:NF-kappa B; D047495:PPAR gamma; D011524:Protoporphyrins; D007649:Ketamine; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000410:Alanine Transaminase