Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 296, Issue 6, Pages G1360-G1369Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00038.2009
Keywords
cyclooxygenase-2; inducible nitric oxide synthase; lipopolysaccharide; carbon monoxide; tin protoporphyrin IX
Categories
Funding
- National Institute of General Medical Sciences [GM-38529, GM-08792]
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P50GM038529, T32GM008792] Funding Source: NIH RePORTER
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Suliburk JW, Ward JL, Helmer KS, Adams SD, Zuckerbraun BS, Mercer DW. Ketamine-induced hepatoprotection: the role of heme oxygenase-1. Am J Physiol Gastrointest Liver Physiol 296: G1360-G1369, 2009. First published April 16, 2009; doi:10.1152/ajpgi.00038.2009.-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 mu mol/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-kappa B 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-kappa B activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO.
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