title: Kupffer cells protect liver from ischemia-reperfusion injury by an inducible nitric oxide synthase-dependent mechanism.
abstract: The aim of this study was to investigate the role of nitric oxide (NO) in rat hepatic ischemia-reperfusion (I/R) injury. Animals were divided into four groups: Group I, control; Group II, gadolinium chloride (GdCl3), a Kupffer cell depleting agent, pretreated; Group III, S-methylisothiourea (SMT), a potent inducible NO synthase (iNOS) inhibitor, pretreated; Group IV, pretreated with SMT, then treated with S-Nitroso-N-acetylpenicillamine (SNAP), a NO donor, after ischemia. Sprague-Dawley rats underwent left lateral and median lobe ischemia for 60 min and reperfusion for 120 min. The left lateral and median lobes were used as ischemic lobes, and the right lateral lobe in the same rat was used as a control lobe. The total NOS (tNOS), iNOS, constitutive NOS (cNOS) activity, and liver protein were determined. The liver tissue malonaldehyde (MDA) level was measured as an index of lipid peroxidation. Liver histology was also examined. The liver tNOS activity in ischemic lobes of Group I, II, III, and IV was increased by 214%, 86%, 61%, and 45%, respectively. The increase in tNOS activity is mainly due to the induction of iNOS activity in the ischemic lobes of rat liver. GdCl3 significantly decreased the tNOS by 66% in the ischemic lobes. GdCl3 significantly increased MDA by 39% in the ischemic lobes. SMT significantly decreased tNOS and iNOS activity by 66% and 85% in ischemic lobes. SMT increased MDA by 67% in the ischemic lobes. SMT + SNAP treatment increased iNOS activity by 117% in the ischemic lobes in comparison with the ischemic lobes of the SMT group. SMT + SNAP treatment decreased MDA by 39% in the ischemic lobes. SMT + SNAP treatment also decreased the sinusoidal congestion and spotty necrosis of hepatocytes in the ischemic lobes. iNOS immunostaining showed an obvious increase in sinusodial area of the ischemic lobes where most Kupffer cells were interspersed. In conclusion, in this model of liver I/R injury, I/R increased the activity of tNOS and iNOS, but not the cNOS activity. Kupffer cells might be the major source of the induction of iNOS activity. The iNOS specific inhibitor SMT increased the lipid peroxidation and the tissue damage in hepatic I/R injury. On the contrary, the NO donor SNAP increased the activity of iNOS and decreased the hepatic injury in this study. Kupffer cells could protect liver from I/R injury by an iNOS-dependent mechanism, thus NO production has a beneficial role in hepatic IR injury.
authors.affiliation: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Ching-Mei
authors.initials: CM
authors.lastname: Hsu
authors.forename: Jyh-Seng
authors.initials: JS
authors.lastname: Wang
authors.forename: Chao-Hsin
authors.initials: CH
authors.lastname: Liu
authors.forename: Lee-Wei
authors.initials: LW
authors.lastname: Chen
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005682:Gadolinium / Q000633:toxicity; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000201:enzymology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000098:blood supply / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D007550:Isothiuronium; D009569:Nitric Oxide; D005682:Gadolinium; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C027744:S-methylisothiopseudouronium; D010396:Penicillamine; C038958:gadolinium chloride