No abstract

Hepatocellular carcinoma (HCC) mostly develops in patients with advanced fibrosis; however, the mechanisms of interaction between a genotoxic insult and fibrogenesis are not well understood. This study tested a hypothesis that fibrosis promotes HCC via a mechanism that involves activation of liver stem cells. First, B6C3F1 mice were administered diethylnitrosamine (DEN; single ip injection of 1mg/kg at 14 days of age). Second, carbon tetrachloride (CCl(4); 0.2ml/kg, 2/week ip starting at 8 weeks of age) was administered for 9 or 14 weeks to develop advanced liver fibrosis. In animals treated with DEN as neonates, presence of liver fibrosis led to more than doubling (to 100%) of the liver tumor incidence as early as 5 months of age. This effect was associated with activation of cells with progenitor features in noncancerous liver tissue, including markers of replicative senescence (p16), oncofetal transformation (Afp, H19, and Bex1), and increased "stemness" (Prom1 and Epcam). In contrast, the dose of DEN used did not modify the extent of liver inflammation, fibrogenesis, oxidative stress, proliferation, or apoptosis induced by subchronic CCl(4) administration. This study demonstrates the potential role of liver stem-like cells in the mechanisms of chemical-induced, fibrosis-promoted HCC. We posit that the combination of genotoxic and fibrogenic insults is a sensible approach to model liver carcinogenesis in experimental animals. These results may contribute to identification of cirrhotic patients predisposed to HCC by analyzing the expression of hepatic progenitor cell markers in the noncancerous liver tissue.

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Renal fibrosis is regarded as the common final pathway leading to chronic kidney diseases; macrophages and myofibroblasts play important roles in the development of fibrosis. F344 rats were injected once with cisplatin (CDDP; 6 mg/kg BW) for renal lesions. Here, immunophenotypical characteristics of macrophages and lymphocytes in CDDP-induced rat renal lesions were investigated histopathologically; the CDDP-induced renal lesions consisted of tissue damage at the early-stage, worsen the damage and commencement of interstitial fibrosis at the mid-stage, and progressive fibrosis at the late stage; the KIM-1 expression and α-SMA+ myofibroblast area reflected renal tubular damage/abnormal regeneration and renal interstitial fibrosis, respectively. CD68+ M1 macrophages began to increase at the mid-stage, with increased mRNA expressions of M1-related cytokines (INF-γ, TNF-α and IL-6), and then slightly decreased at the late-stage. CD163+ M2 macrophages showed a gradually increased number at the mid- and late-stages, accompanied by increased TGF-β1 mRNA expression (a fibrogenic factor). Double immunofluorescence using fibrotic samples at the late-stage revealed that 62.0–78.0% of CD68+ M1 macrophages co-expressed CD163, indicating that M1/M2 macrophages may contribute to progressive renal fibrosis in cooperation; further, MHC class II-expressing macrophages had a tendency towards M1 polarization, whereas CD204-expressing macrophages towards M2 polarization. In addition, CD4+ and CD8+ T cells were increased at the late-stage. Collectively, progressive renal interstitial fibrosis may be developed by complicated mechanisms that arose via interaction of M1/M2 macrophages (inflammatory for M1 and anti-inflammatory for M2) and T cells reacting to CD4 (for helper) and CD8 (for cytotoxicity). This study would provide some information on the pathogenesis of renal fibrosis based on inflammatory cells.

No abstract