The results further identify mTOR as a novel effector of RB of PMNs. Consequently, mTOR inhibition by rapamycin dramatically aggravated the RB defect of patients’ PMNs. This rapamycin-induced inhibition of NOX2 activity in PMNs from patients with cirrhosis was mediated through inhibition of p38-MAPK signaling and phosphorylation of p47phox(S345). Therefore, the use of mTOR inhibitors may increase the susceptibility of patients with cirrhosis to bacterial infections. These results suggest that rapamycin or rapalogs should be used with caution in immuno-depressed patients. The authors thank Margarita Hurtado-Nedelec, Anh Cung, Michèle Fay, and Célia Madjene for their

help with flow cytometry and imaging selleck compound studies. Additional Supporting Information may be found in the online version of this article. “
“Endothelial nitric oxide synthase (eNOS) is a critical modulator of vascular tone and blood flow and plays major roles in liver physiology and pathophysiology. Nitric oxide (NO) is widely recognized as one of the key humoral factors important for the initiation of liver regeneration in response to partial hepatectomy. Liver regeneration in response to partial hepatectomy is dependent on the efficiency of growth factor-mediated cell-cycle progression. Epidermal growth factor receptor (EGFR) is a critical mediator of multiple

hepatic mitogens, such as epidermal growth factor (EGF), transforming growth factor alpha, amphiregulin, and heparin-binding EGF in regenerating livers. However, the functional significance of endothelial nitric AZD1208 mouse oxide synthase (eNOS) expressed in hepatocytes, and its potential role in EGFR-mediated hepatocyte proliferation, remains unexplored. We sought to determine whether eNOS is essential for hepatocyte proliferation in response to partial hepatectomy (PH). Our studies with eNOS knockout (eNOS−/−) mice suggest that eNOS activation is essential for the efficient induction of early events and elicitation of a robust hepatocyte proliferative response to PH. Moreover,

eNOS expression is essential for the efficient early induction of matrix metalloprotease-9, a known mediator of extracellular matrix remodeling and growth factor activation 上海皓元 in regenerating livers. Our in vitro studies suggest that eNOS is a critical mediator of EGF-induced hepatocyte proliferation, potentially via its influence on the induction of early growth response-1 (Egr-1) and phosphorylation of c-Jun—known mediators of cell-cycle progression. EGF-induced eNOS phosphorylation at Ser 1177 is dependent on the phosphorylation and activation of EGFR/PI3 kinase/AKT signaling in hepatocytes. Conclusion: Collectively, these results highlight a hitherto unrecognized role for eNOS activation in hepatocyte proliferation with implications for targeted therapies to enhance liver regenerative response in chronic disorders.