title: Protection against Acute Hepatocellular Injury Afforded by Liver Fibrosis Is Independent of T Lymphocytes.
abstract: Collagen produced during the process of liver fibrosis can induce a hepatocellular protective response through ERK1 signalling. However, the influence of T cells and associated cytokine production on this protection is unknown. In addition, athymic mice are frequently used in hepatocellular carcinoma xenograft experiments but current methods limit our ability to study the impact of liver fibrosis in this setting due to high mortality. Therefore, a mouse model of liver fibrosis lacking T cells was developed using Foxn1 nu/nu mice and progressive oral administration of thioacetamide (TAA) [0.01-0.02%] in drinking water. Fibrosis developed over a period of 16 weeks (alpha-SMA positive area: 20.0 ± 2.2%, preCol1a1 mRNA expression: 11.7 ± 4.1 fold changes, hydroxyproline content: 1041.2 ± 77μg/g of liver) at levels comparable to that of BALB/c mice that received intraperitoneal TAA injections [200 μg/g of body weight (bw)] (alpha-SMA positive area: 20.9 ± 2.9%, preCol1a1 mRNA expression: 13.1 ± 2.3 fold changes, hydroxyproline content: 931.6 ± 14.8μg/g of liver). No mortality was observed. Athymic mice showed phosphorylation of ERK1/2 during fibrogenesis (control 0.03 ± 0.01 vs 16 weeks 0.22 ± 0.06AU; P<0.05). The fibrosis-induced hepatoprotection against cytotoxic agents, as assessed histologically and by serum AST levels, was not affected by the absence of circulating T cells (anti-Fas JO2 [0.5μg/g bw] for 6h (fibrotic 4665 ± 2596 vs non-fibrotic 13953 ± 2260 U/L; P<0.05), APAP [750 mg/kg bw] for 6 hours (fibrotic 292 ± 66 U/L vs non-fibrotic 4086 ± 2205; P<0.01) and CCl4 [0.5mL/Kg bw] for 24h (fibrotic 888 ± 268 vs non-fibrotic 15673 ± 2782 U/L; P<0.001)). In conclusion, liver fibrosis can be induced in athymic Foxn1 nu/nu mice without early mortality. Liver fibrosis leads to ERK1/2 phosphorylation. Finally, circulating T lymphocytes and associated cytokines are not involved in the hepatocellular protection afforded by liver fibrosis.
authors: Laboratoire d'hépatologie cellulaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
authors: Benoit
authors: B
authors: Lacoste
authors: Laboratoire d'hépatologie cellulaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
authors: Valérie-Ann
authors: VA
authors: Raymond
authors: Laboratoire d'hépatologie cellulaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.|Département de Médecine, Université de Montréal, Montréal, QC, Canada.
authors: Pascal
authors: P
authors: Lapierre
authors: Laboratoire d'hépatologie cellulaire, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.|Département de Médecine, Université de Montréal, Montréal, QC, Canada.
authors: Marc
authors: M
authors: Bilodeau
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002273:Carcinogens / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D008099:Liver / Q000187:drug effects; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013601:T-Lymphocytes / Q000502:physiology*; D013853:Thioacetamide / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D002273:Carcinogens; D013853:Thioacetamide