Effects of Hepatocyte CD14 Upregulation during Cholestasis on Endotoxin Sensitivity

Cholestasis is frequently related to endotoxemia and inflammatory response. Our previous investigation revealed a significant increase in plasma endotoxin and CD14 levels during biliary atresia. We therefore propose that lipopolysacharides (LPS) may stimulate CD14 production in liver cells and promote the removal of endotoxins. The aims of this study are to test the hypothesis that CD14 is upregulated by LPS and investigate the pathophysiological role of CD14 production during cholestasis. Using Western blotting, qRT-PCR, and promoter activity assay, we demonstrated that LPS was associated with a significant increase in CD14 and MD2 protein and mRNA expression and CD14 promoter activity in C9 rat hepatocytes but not in the HSC-T6 hepatic stellate cell line in vitro. To correlate CD14 expression and endotoxin sensitivity, in vivo biliary LPS administration was performed on rats two weeks after they were subjected to bile duct ligation (BDL) or a sham operation. CD14 expression and endotoxin levels were found to significantly increase after LPS administration in BDL rats. These returned to basal levels after 24 h. In contrast, although endotoxin levels were increased in sham-operated rats given LPS, no increase in CD14 expression was observed. However, mortality within 24 h was more frequent in the BDL animals than in the sham-operated group. In conclusion, cholestasis and LPS stimulation were here found to upregulate hepatic CD14 expression, which may have led to increased endotoxin sensitivity and host proinflammatory reactions, causing organ failure and death in BDL rats

Portosystemic shunt prevents apoptosis in rat intestinal mucosa caused by total hepatic ischemia

Background: Prolonged splanchnic congestion due to total hepatic ischemia (THI) has been shown to induce damage to the intestinal mucosa. The present study was conducted to examine whether the protective effect of portosystemic shunt (PSS) can be seen on apoptosis of intestinal mucosa in a rat model of THI. Methods: Adult male Wistar rats were divided into the following 3 groups: control group; the THI group underwent THI for 30 min, and the PSS group was subjected to THI for 30 min with PSS. Rats were killed after 1, 2, and 6 h of reperfusion. For each time point, levels of serum liver enzymes, intestinal morphology, malondialdehyde (MDA) contents and DNA fragmentation in intestinal tissue were determined. In addition, the 7-day survival rate was measured. Results: The 7-day survival rate of THI group remained at 50%, whereas that of PSS group was significantly higher at 90% (p < 0.01). Serum AST and ALT levels of the THI and PSS groups rapidly increased after reperfusion, reaching peak values at 2 h. MDA levels after 1 and 2 h of reperfusion in the THI group were significantly increased as compared with the control group p < 0.001). Increases in the percentage of fragmented DNA peaked 1 h after reperfusion in the THI group. PSS resulted in the reduction of DNA fragmentation and preserved the macroscopic and microscopic appearance of the intestinal mucosa. Conclusions: Splanchnic congestion due to portal occlusion increased apoptosis in the rat intestinal mucosa. PSS is very effective in counteracting the principal negative effects of total hepatic ischemia. Copyright (C) 2004 S. Karger AG, Basel

Ergothioneine pretreatment protects the liver from ischemia-reperfusion injury caused by increasing hepatic heat shock protein 70

Background. Reperfusion of the liver after ischemia induces the expression of the heat shock genes and the synthesis of the heat shock proteins (HSP). We studied the effects of the natural antioxidant ergothioneine (EGT) treatment on the expression of HSP70 in ischemic-reperfused (IR) liver

Hemodynamic effects of the early and long-term administration of propranolol in rats with intrahepatic portal hypertension

Background and aims The aims of this study were to evaluate a preventive effect on collateral venous circulation of long-term administration of propranolol in intrahepatic portal hypertensive rats. Methods Eighty-six Sprague–Dawley rats were allocated to two models of hepatic fibrosis, bile duct-ligated (BDL) induced and carbon tetrachloride (CCl4) induced. Each model was divided into two groups: one receiving placebo and the other propranolol (75 mg kg−1 d−1). Mean arterial pressure (MAP), heart rate (HR), portal pressure (PP), cardiac index (CI), vascular systemic resistance, and splenorenal shunt blood flow (SRS-BF) were measured in anesthetized rats. Results In the BDL model, no significant hemodynamic changes were observed in the propranolol group compared with the placebo group. In CCl4-induced rats, HR (390 ± 50 vs. 329 ± 51 beats/min, P = .001), CI (44 ± 11 vs. 34 ± 10 ml/min, P = .004), PP (15.4 ± 3.0 vs. 13.4 ± 1.9 mmHg, P = .045), and SRS-BF (1.4 ± 1.1 vs. 1.0 ± 1.0 ml/min, P = .047) were significantly lower in the propranolol group. Conclusions This study showed that propranolol has a significant hemodynamic effect only in the CCl4 model and suggested a model-dependent effect of propranolol