sirolimus and Liver-Cirrhosis--Alcoholic

De novo malignancies are a main cause for late death after liver transplantation (LT). Everolimus (ERL) is an immunosuppressive agent with antitumoral properties. The aim of the present retrospective study was to identify prognostic factors, including conversion to ERL, for patients presenting non-cutaneous de novo solid organ malignancy after LT for alcoholic cirrhosis. The study population consisted of 83 patients (presenting 100 tumors, including 75% of upper aerodigestive tract cancers), among the 398 patients who underwent LT for alcoholic cirrhosis in our center. After diagnosis, ERL was introduced in 38 patients and calcineurin-inhibitor was discontinued in 64.1% of them. Tumor stage was a significant prognostic factor with a one-yr survival at 82.6% for early stages, 63.4% for intermediate stages (N+) and 27.4% for disseminated diseases (p < 0.001). Associated relative risk factor was 2.202 (95% CI 1.044-4.644) for intermediate stages and 5.743 (95% CI 2.436-13.541) for metastatic stages. One- and five-yr survival was 77.4% and 35.2% in ERL group vs. 47.2% and 19.4% in the non-ERL group, respectively (p = 0.003). The relative risk factor for ERL was 0.447 (95%CI 0.257-0.778). Our results strongly suggest that conversion to ERL improves the prognosis of de novo malignancies after LT for alcoholic cirrhosis. Prospective studies are needed to confirm this benefit.

Topics: Adult; Aged; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Neoplasms; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Sirolimus; Survival Rate

Mitochondrial aldehyde dehydrogenase (ALDH2) plays a critical role in the detoxification of the ethanol metabolite acetaldehyde. This study was designed to examine the impact of global ALDH2 overexpression on alcohol-induced hepatic steatosis.. Wild type Friend virus B (FVB) and ALDH2 transgenic mice were placed on a 4% alcohol or control diet for 12 weeks. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and cholesterol, hepatic triglyceride, steatosis, fat metabolism-related proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signalling were examined. The role of autophagy was evaluated in alcohol dehydrogenase 1 (ADH1)-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without the autophagy inducer rapamycin and lysosomal inhibitors.. Chronic alcohol intake led to elevated AST-, ALT-levels, bilirubin, AST/ALT ratio, cholesterol, hepatic triglycerides and hepatic fat deposition as evidenced by H&E and Oil Red O staining. Hepatic fat deposition was associated with disturbed levels of fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin-6, TNF-α, cyclooxygenase, oxidative stress, and loss of autophagy, effects which were attenuated or ablated by the ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100 and 500 μM) increased levels of IL-6 and IFN-γ, and suppressed autophagy in VA-13 cells, effects which were markedly alleviated by rapamycin. In addition, lysosomal inhibitors mimicked ethanol-induced p62 accumulation with little additive effect with ethanol. Ethanol significantly suppressed LC3 conversion in the presence of lysosomal inhibitors.. In summary, our results revealed that ALDH2 plays a beneficial role in ameliorating chronic alcohol intake-induced hepatic steatosis and inflammation through regulation of autophagy.

Topics: Acetaldehyde; Alcoholism; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Animals; Autophagy; Cholesterol; Cytokines; Female; Hep G2 Cells; Humans; Lipid Metabolism; Liver; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Experimental; Lysosomes; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Transgenic; Multiprotein Complexes; Oxidative Stress; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation

Cirrhosis is commonly accompanied by impaired defense functions of polymorphonuclear leucocytes (PMNs), increased patient susceptibility to infections, and hepatocellular carcinoma (HCC). PMN antimicrobial activity is dependent on a massive production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) 2 (NADPH oxidase 2; NOX2), termed respiratory burst (RB). Rapamycin, an antagonist of mammalian target of rapamycin (mTOR), may be used in the treatment of HCC and in transplanted patients. However, the effect of mTOR inhibition on the PMN RB of patients with cirrhosis remains unexplored and was studied here using the bacterial peptide, formyl-Met-Leu-Phe (fMLP), as an RB inducer. fMLP-induced RB of PMN from patients with decompensated alcoholic cirrhosis was strongly impaired (30%-35% of control) as a result of intracellular signaling alterations. Blocking mTOR activation (phospho-S2448-mTOR) with rapamycin further aggravated the RB defect. Rapamycin also inhibited the RB of healthy PMNs, which was associated with impaired phosphorylation of the NOX2 component, p47phox (phox: phagocyte oxidase), on its mitogen-activated protein kinase (MAPK) site (S345) as well as a preferential inhibition of p38-MAPK relative to p44/42-MAPK. However, rapamycin did not alter the fMLP-induced membrane association of p47phox and p38-MAPK in patients' PMNs, but did prevent their phosphorylation at the membranes. The mTOR contribution to fMLP-induced RB, phosphorylation of p47phox and p38-MAPK was further confirmed by mTOR knockdown in HL-60 cells. Finally, rapamycin impaired PMN bactericidal activity, but not bacterial uptake.. mTOR significantly up-regulates the PMN RB of patients with cirrhosis by p38-MAPK activation. Consequently, mTOR inhibition by rapamycin dramatically aggravates their PMN RB defect, which may increase patients' susceptibility to infection. Thus, concerns should be raised about the use of rapamycin in immuno-depressed patients.

Topics: Antibiotics, Antineoplastic; Cytosol; Drug Interactions; Escherichia coli Infections; Female; HL-60 Cells; Humans; Liver Cirrhosis, Alcoholic; Male; MAP Kinase Signaling System; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; NADPH Oxidases; Neutrophils; p38 Mitogen-Activated Protein Kinases; Phagocytosis; Phosphorylation; Respiratory Burst; Sirolimus; TOR Serine-Threonine Kinases

Sirolimus is a powerful immunosuppressive drug initially used in kidney transplant patients but now increasingly employed in recipients of other types of solid organ transplants, such as liver, heart, lung, or pancreas. Sirolimus is indicated for rescue therapy and to reduce the toxic side effects of calcineurin inhibitors. However, its use has been associated with an uncommon but important pulmonary toxicity. Reports have described interstitial pneumonitis, bronchiolitis obliterans, organizing pneumonia, and alveolar proteinosis. We present the case of a liver transplant patient with interstitial pneumonitis associated with sirolimus.

Topics: Humans; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Lung Diseases, Interstitial; Male; Middle Aged; Sirolimus; Treatment Outcome; Trimethoprim, Sulfamethoxazole Drug Combination