Lipopolysaccharide-Induced Neutrophil Dysfunction Following Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS) Insertion is Associated with Organ Failure and Mortality

Abstract

Systemic lipopolysaccharide (LPS) is implicated in increasing mortality in patients with alcoholic hepatitis but the underlying mechanisms are not well characterised. The objective of this study was to characterise neutrophil function, LPS and cytokine concentrations within the splanchnic circulation of alcoholic cirrhotic patients undergoing TIPSS insertion for variceal haemorrhage and correlate this with outcome. 26 patients with alcoholic cirrhosis and variceal haemorrhage were studied prior to and 1-hour after TIPSS insertion. Neutrophil function, LPS and cytokine concentrations were determined in arterial, hepatic venous (HV) and portal venous blood (PV). Significantly higher LPS concentrations and neutrophil reactive oxidant species (ROS) production were observed in PV vs HV blood. Cross-incubation of HV plasma with PV neutrophils resulted in reduced ROS production. Insertion of TIPSS was associated with a significant increase in arterial LPS concentrations and deterioration in neutrophil phagocytosis. Number of organ failures and arterial IL-6 concentrations at presentation were associated with increased mortality. The portal circulation has a distinct immunological milieu characterised by a pathological neutrophil phenotype and an anti-inflammatory cytokine profile associated with heightened LPS levels. TIPSS insertion renders this neutrophil functional defect systemic, associated with an increase in arterial LPS and a susceptibility to sepsis.

NADPH oxidase depletion in neutrophils from patients with cirrhosis and restoration via toll-like receptor 7/8 activation

“…Thus, strategies based on the activation of intracellular TLR7/8 would be advantageous, compared with those targeting surface receptors. Supporting this concept, the TLR7/8 agonist R848 reduced mortality in mice with sepsis,51 unlike LPS which provides adverse effects 50…”

“…This discrepancy is possibly related to the phenomenon of homologous or heterologous desensitisation of membrane receptors of patients’ neutrophils due to their exposure to blood LPS, as suggested by the inability of LPS and fMLP to stimulate ROS production in patients’ neutrophils, unlike healthy neutrophils (figure 6C,D). This phenomenon may also explain the fact that LPS induces neutrophil dysfunction associated with organ failure and mortality 50. Thus, strategies based on the activation of intracellular TLR7/8 would be advantageous, compared with those targeting surface receptors.…”

Innate immune cells in cirrhosis

“…25 The impairment of neutrophil's defence function comprises both intracellular and extracellular alterations. The intrinsic neutrophil impairments reported above (Table 1) can be reproduced with pathological concentrations of various agents present in patient serum such as bilirubin, 27 hyperammonemia and hyponatremia, 35 elastase, 18,34 prostaglandin E2 (PGE2 36 ), LPS 28,37 or anti-inflammatory cytokines (IL-4, IL-10, transforming growth factor-beta [TGFb]). These deficiencies are likely to be aggravated in ALD 28 since ethanol by itself causes transphosphatidylation, a phospholipase D-catalysed reaction which generates a biologically inactive metabolite, phosphatidylethanol, instead of phosphatic acid.…”