Arginine reverses ethanol-induced inflammatory and fibrotic changes in liver despite continued ethanol administration.
We investigated the potential of arginine to reverse pathological changes in alcohol-induced liver injury. Four groups (six rats/group) of male Wistar rats were fed a fish oil-ethanol diet for 6 (group 2) or 8 (group 1) weeks. Rats in group 3 were fed fish oil-ethanol for 6 weeks, after which they were administered arginine with fish oil-ethanol for an additional 2 weeks. Rats in group 4 were fed fish oil-dextrose for 8 weeks. Liver samples were analyzed for histopathology, lipid peroxidation, cytochrome P4502E1 activity, nuclear factor-kappaB, and levels of messenger RNA for tumor necrosis factor-alpha, cyclooxygenase-2, and inducible nitric oxide synthase. Concentrations of endotoxin were measured in plasma. The most severe inflammation and fibrosis was detected in groups 1 and 2, as were the highest levels of endotoxin, lipid peroxidation, cytochrome P450 2E1 activity, activation of nuclear factor-kappaB, and mRNA levels for tumor necrosis factor-alpha, cyclooxygenase-2, and inducible nitric oxide synthase. Plasma nitric oxide was also increased as was nitrotyrosine in liver. After arginine was administered, there was marked improvement in the pathological changes accompanied by decreased levels of endotoxin, lipid peroxidation, activation of nuclear factor-kappaB, tumor necrosis factor-alpha, cyclooxygenase-2, inducible nitric oxide, and nitrotyrosine staining. The therapeutic effects of arginine are probably secondary to increased levels of nitric oxide but other effects of arginine cannot be excluded.
Nanji
A A
AA
Department of Pathology and Centre for The Study of Liver Diseases, University of Hong Kong and Queen Mary Hospital, Hong Kong. ananji@pathology.hku.hk
Jokelainen
K
K
Lau
G K
GK
Rahemtulla
A
A
Tipoe
G L
GL
Polavarapu
R
R
Lalani
E N
EN
D000818:Animals; D001120:Arginine / Q000627:therapeutic use*; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D015536:Down-Regulation; D004347:Drug Interactions; D004731:Endotoxins / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000517:prevention & control; D007527:Isoenzymes / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008104:Liver Cirrhosis, Alcoholic / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D004731:Endotoxins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D000431:Ethanol; D014443:Tyrosine; D001120:Arginine; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases