Inhibition of mammalian target of rapamycin aggravates the respiratory burst defect of neutrophils from decompensated patients with cirrhosis

• DOI: 10.1002/hep.26109
• Publication Date: 2012-10-18T19:29:09Z
• Authors: Loïc Rolas; Nesrine Makhezer; Soumeya Hadjoudj; Jamel El-Benna; Bahia Djerdjouri; Laure Elkrief; Richard Moreau; Axel Périanin
• Keywords: Sirolimus

Cirrhosis is commonly accompanied by impaired defense functions of polymorphonuclear leucocytes (PMNs), increased patient susceptibility to infections, and hepatocellular carcinoma (HCC). PMN antimicrobial activity dependent on a massive production reactive oxygen species (ROS) nicotinamide adenine dinucleotide phosphate (NADPH) 2 (NADPH oxidase 2; NOX2), termed respiratory burst (RB). Rapamycin, an antagonist mammalian target rapamycin (mTOR), may be used in the treatment HCC transplanted patients. However, effect mTOR inhibition RB patients with cirrhosis remains unexplored was studied here using bacterial peptide, formyl-Met-Leu-Phe (fMLP), as inducer. fMLP-induced from decompensated alcoholic strongly (30%-35% control) result intracellular signaling alterations. Blocking activation (phospho-S2448-mTOR) further aggravated defect. Rapamycin also inhibited healthy PMNs, which associated phosphorylation NOX2 component, p47 phox (phox: phagocyte oxidase), its mitogen-activated protein kinase (MAPK) site (S345) well preferential p38-MAPK relative p44/42-MAPK. did not alter membrane association patients' but prevent their at membranes. The contribution RB, confirmed knockdown HL-60 cells. Finally, bactericidal activity, uptake. Conclusion : significantly up-regulates activation. Consequently, dramatically aggravates defect, increase infection. Thus, concerns should raised about use immuno-depressed (Hepatology 2013)