Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγnull mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12+IL-10−CD163−CD14+ cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1+CD163+CD14+ cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12−IL-10−CCL1−CD163−CD14+ cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes.

Nonalcoholic fatty liver disease (NAFLD) can develop into end-stage disease that includes cryptogenic cirrhosis and hepatocellular carcinoma. Bacterial endotoxin, for example lipopolysaccharide (LPS), plays an important role in the pathogenesis of NAFLD. The aim of this study was to assess the role of LPS in the development of NAFLD. Twenty-one male Zucker (fa/fa) rats were divided into three groups: rats fed for twelve weeks on a diet rich in disaccharide (D12 group), rats similarly managed but treated with LPS (LPS group), and those on the same diet for 24 weeks (D24 group). Histological examination demonstrated that this protocol induced hepatic steatosis in the LPS and D24 groups. Significant, marked accumulation of lipid droplets was observed in the LPS group, compared with the D24 group. Rats from the LPS group showed a decrease in plasma adiponectin levels, an increase in plasma leptin levels, and greater expression of FAS and SREBP-1c mRNA in the liver, compared with rats from the D24 group. These finding coincided with histological findings. We therefore suggest that LPS may accelerate the progression of hepatic steatosis.

Despite major advances in curative and palliative approaches, hepatocellular carcinoma (HCC) is still the third leading cause of cancer-related death worldwide. M1 macrophages (Mf) play a key role in host antitumor defenses in HCC. In our study, CD14

Hepatocellular carcinoma (HCC) represents approximately 85% of all primary liver cancer cases. Non-alcoholic fatty liver disease (NAFLD) is one of the risk factors for HCC. NAFLD occurs in patients with components of metabolic syndrome, such as type 2 diabetes mellitus, obesity, hypertension and hyperlipidemia. Therefore, hyperlipidemia also represents a patient population at risk for HCC that can readily be identified. Rosuvastatin, a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor, has exhibited a more potent affinity for the active site of HMG-CoA reductase than other statins. In addition, the hepatic uptake of rosuvastatin in rats has been found to be more selective and efficient than that with other drugs. Furthermore, the cytoprotective effects of rosuvastatin against ischemic injury have been clearly reported. Thus, in this study, we aimed to determine the role of rosuvastatin as a preventive drug in HCC associated with NAFLD. STAM mice, which developed HCC from NAFLD by being fed a high-fat diet (HFD), were divided into a group in which a HFD was given to the mice for 15 weeks (n=8) and another in which a HFD supplemented with 0.00125% rosuvastatin was given to the mice for 15 weeks (n=8). Rosuvastatin inhibited the development of hepatic tumors in the mice with NAFLD induced by a specific diet both macroscopically and histologically. Rosuvastatin significantly decreased the expression levels of pro-inflammatry cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and transforming growth factor (TGF)-β1. Tumor aggressiveness is mediated by angiogenic factors. Therefore, we examined the hepatic mRNA expression of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and platelet-derived growth factor (PDGF). The hepatic expression of these factors significantly decreased in the rousvastin-fed mice. Our results thus suggest rosuvastatin that prevents carcinogenesis and improves the hepatic background. Our data suggest that rosuvastatin has potential for use as a preventive drug for the development of HCC associated with NAFLD in mice.

Transarterial chemoembolization (TACE) is usually followed by hepatic dysfunction. We evaluated the effects of L-carnitine on post-TACE impaired liver functions. Methods. 53 cirrhotic hepatocellular carcinoma patients at Osaka Medical College were enrolled in this study and assigned into either L-carnitine group receiving 600 mg oral L-carnitine daily or control group. Liver functions were evaluated at pre-TACE and 1, 4, and 12 weeks after TACE. Results. The L-carnitine group maintained Child-Pugh (CP) score at 1 week after TACE and exhibited significant improvement at 4 weeks after TACE (P < 0.01). Conversely, the control group reported a significant CP score deterioration at 1 week (P < 0.05) and 12 weeks after TACE (P < 0.05). L-carnitine suppressed serum albumin deterioration at 1 week after TACE. There were significant differences between L-carnitine and control groups regarding mean serum albumin changes from baseline to 1 week (P < 0.05) and 4 weeks after TACE (P < 0.05). L-carnitine caused prothrombin time improvement from baseline to 1, 4 (P < 0.05), and 12 weeks after TACE. Total bilirubin mean changes from baseline to 1 week after TACE exhibited significant differences between L-carnitine and control groups (P < 0.05). The hepatoprotective effects of L-carnitine were enhanced by branched chain amino acids combination. Conclusion. L-carnitine maintained and improved liver functions after TACE.