title: Role of nitric oxide in the regulation of fibrogenic factors in experimental liver fibrosis in mice.
abstract: Previously, we have shown that an increased expression level of iNOS but a reduction in the expression of eNOS is associated with increased oxidative stress markers in CCl₄-induced experimental liver fibrosis. The present study aimed to investigate the effect of L-arginine and 5-methylisothiourea hemisulfate (SMT) in the expression of profibrogenic factors in chronic liver injury. ICR mice were treated with CCl₄ with or without treatment of L-arginine, an NO donor, or SMT, an iNOS inhibitor. The expression of matrix metalloptroteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), α-smooth muscle actin (α-SMA), tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2) were investigated by RT-PCR. The activity of the MMP-2 and MMP-9 were measured by zymography. Our results showed that CCl₄-treated mice showed significant up-regulation of expression of pro-fibrogenic factors, TNF-α and COX-2. Treatment with L-arginine or SMT showed a significant reduction in CCl₄-induced expression of these pro-fibrogenic factors, TNF-α and COX-2. In conclusion, both SMT and L-arginine effectively attenuated the progression of CCl₄-induced liver fibrosis. SMT suppresses iNOS mediated NO production. However, L-arginine augments NO production. The similar effect of the two drugs on liver fibrosis indicates that there may be two distinct pathways of NOS mediated fibrogenesis in chronic liver injury by iNOS and eNOS. Our results suggest that eNOS-mediated liver fibrogenesis may play a more important role than that of iNOS in chronic liver injury. Taken together, these results support the contention that NO plays an active role in the progression of liver fibrosis and hepatocellular damage.
authors.affiliation: Department of Pathology and Laboratory Medicine, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
authors.forename: Tung-Ming
authors.initials: TM
authors.lastname: Leung
authors.forename: Man-Lung
authors.initials: ML
authors.lastname: Fung
authors.forename: Emily C
authors.initials: EC
authors.lastname: Liong
authors.forename: Thomas Y H
authors.initials: TY
authors.lastname: Lau
authors.forename: Amin A
authors.initials: AA
authors.lastname: Nanji
authors.forename: George L
authors.initials: GL
authors.lastname: Tipoe
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D015415:Biomarkers; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000199:Actins; D015415:Biomarkers; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007550:Isothiuronium; D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C027744:S-methylisothiopseudouronium