Conclusion: mTOR significantly up-regulates the PMN RB of patients with

cirrhosis by p38-MAPK activation. Consequently, mTOR inhibition by rapamycin dramatically aggravates their PMN BVD-523 solubility dmso RB defect, which may increase patients’ susceptibility to infection. Thus, concerns should be raised about the use of rapamycin in immuno-depressed patients. (HEPATOLOGY 2013) Reactive oxygen species (ROS) produced by polymorphonuclear leukocytes (PMNs), monocytes or macrophages, termed respiratory burst (RB) or oxidative stress (OS), play a key role in antimicrobial host-defense systems.1 The enzyme responsible for the phagocyte RB, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), is a membrane multiprotein complex whose activation requires the phosphorylation and membrane translocation of cytosolic components, among which p47phox (phox: phagocyte oxidase) plays an important role.2 In pathological situations, ROS production becomes inappropriately regulated. An excessive production of ROS induces tissue damage, which has been implicated in various diseases,1 including hepatic fibrosis.3 A deficient production Sorafenib research buy of ROS promotes patients’ susceptibility to microbial infections.1 Cirrhosis is a typical example in which inappropriate ROS production induces both tissue damage and patient susceptibility to infections.4 PMNs have been shown to contribute to liver injury in animal

models5 and patients with alcoholic hepatitis.6 In these patients, the level of intrahepatic expression of “neutrophil-attractant” CXC chemokines, interleukin-8 and ENA-78 (CXCL5), have been shown to correlate with poor survival.7 Direct evidence for the importance of ROS in PMN-induced liver injury is provided by the observation of an intracellular OS in hepatocytes during the PMN infiltration8 and in p47phox knockout mice.3 A common complication of liver fibrosis is the development of sepsis, a major cause of death,9 which is associated with impaired PMN RB, microbicidal activity, and phagocytosis.10 PMN Buspirone HCl dysfunctions were found to be reversible after endotoxin removal from

patient plasma.11 In other studies, persistent cellular defects were also observed.12 An impaired RB of PMN was also reported in liver transplant recipients suffering from posthepatitic cirrhosis.13 Rapamycin is used clinically for various purposes because of its ability to antagonize the kinase activity of mammalian target of rapamycin (mTOR). Inhibition of mTOR is under evaluation in patients with hepatocellular carcinoma (HCC).14, 15 Moreover, because there is some experimental evidence that mTOR is involved in portal hypertension (PH)-associated angiogenesis, it has been suggested that mTOR inhibtion could be a target for future therapies in PH.16, 17 Rapamycin is also used as an immunosuppressive drug to prevent rejection of transplanted organs.