Abstract
Patients with decompensated cirrhosis are highly susceptible to develop bacterial infections and these can trigger multiorgan failure associated with high in-hospital mortality. Neutrophils from patients with decompensated cirrhosis exhibit marked alterations that may explain the susceptibility of these patients to develop bacterial infections. These neutrophil alterations include marked defects in intracellular signaling pathways involving serine/threonine kinases such as protein kinase B (AKT), p38-mitogen-activated protein kinase (MAPK), and the MAP kinases1/2; activation of the NADPH oxidase complex; myeloperoxidase (MPO) release; and bactericidal activity of neutrophils stimulated by the bacterial peptide formyl-Methionine-Leucine-Phenylalanine (fMLF). Impaired activity of the NADPH oxidase 2 (NOX2) complex is also related to reduced levels of expression of its major components through post-transcriptional mechanisms. In addition, the catalytic NOX2 component gp91phox is subject to degradation by elastase highly present in patients' plasma. A defect in the protein kinase B (AKT) and p38 MAPK-mediated signaling pathways may explain the decrease in phosphorylation of p47phox (an important component of the NADPH oxidase complex) and MPO release, in response to neutrophil stimulation by fMLF. Most of these alterations are reversible ex vivo with TLR7/8 agonists (CL097, R848), raising the possibility that these agonists might be used in the future to restore neutrophil antibacterial functions in patients with cirrhosis.
Highlights
The natural history of cirrhosis, the most common chronic liver disease, is characterized by episodes of acute decompensation [1]
Studies have shown that neutrophils from patients with cirrhosis exhibit ex vivo defective adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) [3,4,5] and of myeloperoxidase (MPO) exocytosis [4], which both may contribute to the susceptibility to infection in patients with cirrhosis
The defects in O−2 . production, MPO release, decreased phosphorylation of AKT, p38 mitogen-activated protein kinase (MAPK), and bactericidal activity in patients’ neutrophils can be reversed ex vivo by treatment of patients’ neutrophils with toll-like receptor 7/8 (TLR7/8) agonists [4, 5]. This treatment stimulates a rapid CYBB transcription and translation into gp91phox which is inhibited by rapamycin, indicating a mammalian target of rapamycin (mTOR)-dependent process. These findings suggest that TLR7/8 agonists might be used in the future to restore neutrophil functions in patients with decompensated alcoholic cirrhosis
Summary
The natural history of cirrhosis, the most common chronic liver disease, is characterized by episodes of acute decompensation (e.g., development of ascites, gastrointestinal hemorrhage, or hepatic encephalopathy) [1]. Following fMLF stimulation, neutrophils from patients have decreased phosphorylation (i.e., activation) of AKTs, p38-MAPK, and ERK1/2 with no changes in the expression levels of corresponding unphosphorylated proteins and in the expression of the formyl peptide receptor [(3, 4), Figure 1B] Together these findings suggest the existence of an important defect in signaling pathway, somewhere between the surface receptor and effector proteins. Production, MPO release, decreased phosphorylation of AKT, p38 MAPK, and bactericidal activity in patients’ neutrophils can be reversed ex vivo by treatment of patients’ neutrophils with toll-like receptor 7/8 (TLR7/8) agonists [4, 5] This treatment stimulates a rapid CYBB transcription and translation into gp91phox which is inhibited by rapamycin, indicating a mTOR-dependent process. The efficacy and safety of TLR7/8 agonists should be further investigated in vivo preclinical experiments performed in mouse models of chronic liver disease
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