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Hepatic injury induced by ischemia and reperfusion is an important clinical problem after liver resection or transplantation. Neutrophils are known to mediate the organ injury, but the precise mechanisms leading to hepatic neutrophil recruitment are undefined. Two CXC chemokines, macrophage inflammatory protein-2 (MIP-2) and KC, are potently chemotactic for neutrophils in vitro and have been reported to be involved in neutrophil-dependent inflammatory tissue injury. The objective of the present study was to determine the roles of MIP-2 and KC in the induction of hepatic ischemia/reperfusion injury. C57BL/6 mice were subjected to 90 minutes of partial hepatic ischemia followed by reperfusion. Hepatic injury was associated with neutrophil sequestration, edema, and elevated serum levels of hepatic transaminases. The expression of MIP-2 messenger RNA (mRNA) was induced within 3 hours after reperfusion, before any detectable increase in neutrophil accumulation, and was also increased to a greater extent in the ischemic lobe after 9 hours of reperfusion. These data suggest that MIP-2 may be involved in the initial recruitment of neutrophils to the ischemic lobe. In contrast, KC mRNA expression was not increased after 3 hours of reperfusion but after 9 hours increased equivalently in both ischemic and nonischemic lobes, suggesting a more generalized role in neutrophil recruitment. Neutralization of MIP-2 or KC resulted in significant decreases in hepatic neutrophil accumulation, edema, and hepatocellular injury. These data suggest that the local expression of MIP-2 and KC are important mediators involved in neutrophil-dependent hepatic injury induced by ischemia and reperfusion in mice. (HEPATOLOGY 1998;27:507-512.)Hepatic injury caused by ischemia and reperfusion during surgical resection or transplantation of the liver may lead to both local and systemic organ dysfunction. The local hepatic injury is comprised of two phases, with the initial injury being mediated by activated Kupffer cells. 1,2 Neutrophils are primed during this initial period and play a central role in the ensuing hepatic injury. The temporal involvement of Kupffer cells and neutrophils has been reported by studies in which neutropenic rats incurring hepatic ischemia and reperfusion experienced early injury but were protected from subsequent hepatic damage. 3 The accumulation of neutrophils may result in hepatic hypoperfusion, which is caused by sinusoidal occlusion, 4 and the release of reactive oxygen and proteases by neutrophils may also promote progressive hepatocellular damage. 5 However, the mechanisms by which ischemia and reperfusion induce neutrophil accumulation and the subsequent hepatic injury are undefined.Increased production of tumor necrosis factor-␣ is associated with neutrophil-dependent liver injury after hepatic ischemia and reperfusion. 6 The local production of tumor necrosis factor-␣ is increased after hepatic ischemia and reperfusion; and while tumor necrosis factor-␣ itself does not induce neutrophil chemotaxis, recent studi...

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These results suggest that the intraductal growth type of tumour should be treated as a distinct entity compared with other types of ICC. Multiple tumours and high serum CA19-9 level were signs of dismal prognosis, whereas not all patients with lymph node involvement had a poor prognosis.

BackgroundAlthough fibroblast growth factor 19 (FGF19) can promote liver carcinogenesis in mice, its involvement in human hepatocellular carcinoma (HCC) has not been well investigated. FGF19, a member of the FGF family, has unique specificity for its receptor FGFR4. This study aimed to clarify the involvement of FGF19 in the development of HCC.MethodsWe investigated human FGF19 and FGFR4 expression in 40 hepatocellular carcinoma specimens using quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) analysis and immunohistochemistry. Moreover, we examined the expression and the distribution of FGF19 and FGFR4 in 5 hepatocellular carcinoma cell lines (HepG2, HuH7, HLE, HLF, and JHH7) using RT-PCR and immunohistochemistry. To test the role of the FGF19/FGFR4 system in tumor progression, we used recombinant FGF19 protein and small interfering RNA (siRNA) of FGF19 and FGFR4 to regulate their concentrations.ResultsWe found that FGF19 was significantly overexpressed in HCCs as compared with corresponding noncancerous liver tissue (P < 0.05). Univariate and multivariate analyses revealed that the tumor FGF19 mRNA expression was an independent prognostic factor for overall and disease-free survival. Moreover, we found that the FGF19 recombinant protein could increase the proliferation (P < 0.01, n = 12) and invasion (P < 0.01, n = 6) capabilities of human hepatocellular carcinoma cell lines and inhibited their apoptosis (P < 0.01, n = 12). Inversely, decreasing FGF19 and FGFR4 expression by siRNA significantly inhibited proliferation and increased apoptosis in JHH7 cells (P < 0.01, n = 12). The postoperative serum FGF19 levels in HCC patients was significantly lower than the preoperative levels (P < 0.01, n = 29).ConclusionsFGF19 is critically involved in the development of HCCs. Targeting FGF19 inhibition is an attractive potential therapeutic strategy for HCC.