Granulocyte-macrophage colony-stimulating factor (GM-CSF) shows therapeutic effect on dimethylnitrosamine (DMN)-induced liver fibrosis in rats

• Published in: PloS one Vol. 17; no. 9; p. e0274126
• Main Authors: Karmacharya, Mrigendra Bir, Hada, Binika, Park, So Ra, Kim, Kil Hwan, Choi, Byung Hyune
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 02-09-2022; Public Library of Science (PLoS)
• Subjects: Actin; Albumins; Antibodies; Aspartate aminotransferase; Bilirubin; Biology and Life Sciences; Body weight; Collagen; Collagen (type I); Colonies; Colony-stimulating factor; Cytokines; Fibroblasts; Fibrosis; Granulocyte-macrophage colony stimulating factor; Granulocytes; Growth factors; Hepatitis; Injuries; Liver; Medicine and Health Sciences; Muscles; N-Nitrosodimethylamine; Peroxisome proliferator-activated receptors; Physical Sciences; Proteins; Research and Analysis Methods; Rodents; Serum levels; Smooth muscle; Survival; Transforming growth factor-a; Transforming growth factor-b1; Wound healing; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0274126

This study was undertaken to investigate the inhibitory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. Liver fibrosis was induced in Sprague-Dawley rats by injecting DMN intraperitoneally (at 10 mg/kg of body weight) daily for three consecutive days per week for 4 weeks. To investigate the effect of GM-CSF on disease onset, GM-CSF (50 μg/kg of body weight) was co-treated with DMN for 2 consecutive days per week for 4 weeks (4-week groups). To observe the effect of GM-CSF on the progression of liver fibrosis, GM-CSF was post-treated alone at 5–8 weeks after the 4 weeks of DMN injection (8-week groups). We found that DMN administration for 4 weeks produced molecular and pathological manifestations of liver fibrosis, that is, it increased the expressions of collagen type I, alpha-smooth muscle actin (α-SMA), and transforming growth factor-β1 (TGF-β1), and decreased peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. In addition, elevated serum levels of aspartate aminotransferase (AST), total bilirubin level (TBIL), and decreased albumin level (ALB) were observed. In both the 4-week and 8-week groups, GM-CSF clearly improved the pathological liver conditions in the gross and histological observations, and significantly recovered DMN-induced increases in AST and TBIL and decreases in ALB serum levels to normal. GM-CSF also significantly decreased DMN-induced increases in collagen type I, α-SMA, and TGF-β1 and increased DMN-induced decreases in PPAR-γ expression. In the DMN groups, survival decreased continuously for 8 weeks after DMN treatment for the first 4 weeks. GM-CSF showed a survival benefit when co-treated for the first 4 weeks but a marginal effect when post-treated for 5–8 weeks. In conclusion, co-treatment of GM-CSF showed therapeutic effects on DMN-induced liver fibrosis and survival rates in rats, while post-treatment efficiently blocked liver fibrosis.