Introduction Activation of systemic inflammatory responses in acetaminophen-induced acute liver failure (AALF) is associated with elevated levels of both pro- and anti-inflammatory cytokines. Functional monocyte deactivation has been described and this is thought to contribute to increased susceptibility to sepsis and a higher mortality rate. Anti-inflammatory cytokines play a major part in the resolution of inflammatory responses and promote tissue repair processes but increase the risk of systemic infections. We hypothesise that the levels of anti-inflammatory cytokines mirror the severity of hepatic necrosis and reflect attempts to resolve inflammation during AALF. It is the excessive production of these mediators that “spill-over” and increase the risk of systemic sepsis. We sought to delineate hepatic and systemic cytokine responses in experimental and human AALF, and, determine whether there is production of anti-inflammatory cytokines in the liver which “spill-over” into the systemic circulatory compartment.
Aim We sought to delineate hepatic and systemic inflammatory responses in experimental and human AALF, and, determine whether there is a “spill-over” of hepatic anti-inflammatory mediators into the systemic, circulatory, compartment.
Method Median levels (pg/ml) of hepatic IL-1ß, IL-4,-6,-10,-12,-17, IFN-Y, MCP-1, TNF-α, TGF-ß1 were measured using proteome arrays in 10 human AALF explants and 8 normal control liver tissue samples.
Hepatic and serum levels of IL-1ß, IL-4,-6,-10,-12,-17, MCP-1, TNF-α, TGF-ß1 were measured in 200mg/kg i.p. APAP treated male C3H/HeH mice (n=5 severe necrosis, n=5 moderate necrosis) and 5 control mice.
Regional levels (portal vein (PV)), hepatic vein (HV), arterial (art)) of TNF-α, IL-10 were determined using ELISA in 3 AALF patients at time of liver transplantation.
Results In human AALF, hepatic levels of IL-6 (115 vs 75; p=0.02), IL-10 (1.8 vs 0.6; p=0.03), TGF-ß1 (3009 vs 1323; p<0.0001) were elevated in AALF compared to controls while IL-1ß, IL-12, IL-17, IFN-Y and TNF-α were unchanged. Higher hepatic levels of IL-4 (37 vs 25; p<0.01), IL-10 (90 vs 66; p<0.01), IL-12 (11 vs 7.8; p<0.01) and TGF-ß1 (2521 vs 540; p<0.01) were detected in mice with severe hepatic necrosis compared to those with moderate necrosis and normal controls. Similar to human AALF, serum pro- (IL-6 (146 vs 13; p<0.01), IL-1ß (104 vs 62 (p=0.07)) and anti-inflammatory cytokines (IL-4 (3 vs 0.8; p<0.01), IL-10 (47 vs 1; p<0.01) were elevated compared to normal controls during murine AALF.
Conclusion We demonstrate a hepatic inflammatory microenvironment favouring resolution of inflammation/tissue repair processes. In vivo hepatic production and systemic “spill-over” of the immunosupressive cytokines is observed and may account for functional monocyte deactivation and the marked predisposition to sepsis in AALF. The marked similarities in anti-inflammatory mediator profiles between human and murine models of AALF provide a rationale on which to base the studies examining evolution of disease and development of immunomodulatory strategies to ameliorate acute liver injury and promote tissue repair.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.