Reduced post‐operative neutrophil activation in liver transplant recipients suffering from post‐hepatitic cirrhosis

Jüttner, Björn; Younes, Alan; Weissig, Annette; Ahrens, Jörg; Becker, Thomas; Scheinichen, Dirk

doi:10.1111/j.1399-0012.2009.01016.x

Cited by 6 publications

(5 citation statements)

References 28 publications

(34 reference statements)

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“…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…”

mentioning

confidence: 64%

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

et al. 2013

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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. 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 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)

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“…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…”

mentioning

confidence: 64%

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

et al. 2013

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“…Patients with cirrhosis have impaired neutrophilic ROS production, as well as phagocytotic and microbicidal activities [ 176 , 177 , 178 ]. Post-hepatic cirrhosis has also been observed to be closely related to diminished ROS production in some liver transplant recipients [ 179 ]. The mechanism of impaired signaling events of neutrophils in relation to alcoholic cirrhosis is not fully understood.…”

Section: Role Of Myeloperoxidase In Different Diseasesmentioning

confidence: 99%

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

2018

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Myeloperoxidase (MPO) belongs to the family of heme-containing peroxidases, produced mostly from polymorphonuclear neutrophils. The active enzyme (150 kDa) is the product of the MPO gene located on long arm of chromosome 17. The primary gene product undergoes several modifications, such as the removal of introns and signal peptides, and leads to the formation of enzymatically inactive glycosylated apoproMPO which complexes with chaperons, producing inactive proMPO by the insertion of a heme moiety. The active enzyme is a homodimer of heavy and light chain protomers. This enzyme is released into the extracellular fluid after oxidative stress and different inflammatory responses. Myeloperoxidase is the only type of peroxidase that uses H2O2 to oxidize several halides and pseudohalides to form different hypohalous acids. So, the antibacterial activities of MPO involve the production of reactive oxygen and reactive nitrogen species. Controlled MPO release at the site of infection is of prime importance for its efficient activities. Any uncontrolled degranulation exaggerates the inflammation and can also lead to tissue damage even in absence of inflammation. Several types of tissue injuries and the pathogenesis of several other major chronic diseases such as rheumatoid arthritis, cardiovascular diseases, liver diseases, diabetes, and cancer have been reported to be linked with MPO-derived oxidants. Thus, the enhanced level of MPO activity is one of the best diagnostic tools of inflammatory and oxidative stress biomarkers among these commonly-occurring diseases.

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“…Of the numerous circulating host-defense mechanisms available, neutrophil production of ROS, microbicidal activity and phagocytosis are impaired in cirrhotic patients [27][28][29][30][31][32][33][34][35]. An impaired ROS production was also observed in liver transplanted recipients suffering from post-hepatitic cirrhosis [36]. However, the impact of alcoholic cirrhosis on receptor-mediated signaling events underlying neutrophil antibacterial activities remains largely unknown.…”

Section: Introductionmentioning

confidence: 97%

Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis

Boussif

Rolas

Weiss

et al. 2016

Journal of Hepatology

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Reduced post‐operative neutrophil activation in liver transplant recipients suffering from post‐hepatitic cirrhosis

Cited by 6 publications

References 28 publications

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

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

Myeloperoxidase as an Active Disease Biomarker: Recent Biochemical and Pathological Perspectives

Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis

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