Dataset Information

Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure.

ABSTRACT: Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the initial mechanisms of toxicity are well described, a debate has recently occurred in the literature over whether there is a second phase of injury, mediated by inflammatory processes. Critical to this potential inflammatory process is the activation of caspase-1 and interleukin-1? by a molecular complex known as the inflammasome. Several different stimuli for the formation of multiple different inflammasome complexes have been identified. Formation of the NACHT, leucine-rich repeat (LRR) and pyrin (PYD) domains-containing protein 3 (Nalp3) inflammasome in particular, has directly been attributed to late-stage acetaminophen toxicity. In this review, we will discuss the mechanisms of acetaminophen-induced liver injury in mice and man with a particular focus on the role of inflammation and the inflammasome.

SUBMITTER: Woolbright BL

PROVIDER: S-EPMC5362341 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure.

Woolbright Benjamin L BL Jaeschke Hartmut H

Journal of hepatology 20161129 4

Drug-induced acute liver failure carries a high morbidity and mortality rate. Acetaminophen overdose is the number one cause of acute liver failure and remains a major problem in Western medicine. Administration of N-acetyl cysteine is an effective antidote when given before the initial rise in toxicity; however, many patients present to the hospital after this stage occurs. As such, treatments which can alleviate late-stage acetaminophen-induced acute liver failure are imperative. While the ini ...[more]

PMID: 27913221

Similar Datasets

Project description:IntroductionSystemic levels of the anti-inflammatory cytokine interleukin 10 (IL-10) are highest in acetaminophen (APAP)-induced acute liver failure (ALF) patients with the poorest prognosis. The mechanistic basis for this counterintuitive finding is not known, as induction of IL-10 is hypothesized to temper the pathological effects of immune cell activation. Aberrant production of IL-10 after severe liver injury could conceivably interfere with the beneficial, pro-reparative actions of immune cells, such as monocytes.MethodsTo test this possibility, we determined whether IL-10 levels are dysregulated in mice with APAP-induced ALF and further evaluated whether aberrant production of IL-10 prevents monocyte recruitment and/or the resolution of necrotic lesions by these cells.ResultsOur studies demonstrate that in mice challenged with 300 mg/kg acetaminophen (APAP), a hepatotoxic dose of APAP that fails to produce ALF (i.e., APAP-induced acute liver injury; AALI), Ly6Chi monocytes were recruited to the liver and infiltrated the necrotic lesions by 48 hours coincident with the clearance of dead cell debris. At 72 hours, IL-10 was upregulated, culminating in the resolution of hepatic inflammation. By contrast, in mice treated with 600 mg/kg APAP, a dose that produces clinical features of ALF (i.e., APAP-induced ALF; AALF), IL-10 levels were markedly elevated by 24 hours. Early induction of IL-10 was associated with a reduction in the hepatic numbers of Ly6Chi monocytes resulting in the persistence of dead cell debris. Inhibition of IL-10 in AALF mice, beginning at 24 hours after APAP treatment, increased the hepatic numbers of monocytes which coincided with a reduction in the necrotic area. Moreover, pharmacologic elevation of systemic IL-10 levels in AALI mice reduced hepatic myeloid cell numbers and increased the area of necrosis.DiscussionCollectively, these results indicate that during ALF, aberrant production of IL-10 disrupts the hepatic recruitment of monocytes, which prevents the clearance of dead cell debris. These are the first studies to document a mechanistic basis for the link between high IL-10 levels and poor outcome in patients with ALF.

Project description:OBJECTIVE:To evaluate the role of hepatocellular and extrahepatic apoptosis during the evolution of acetaminophen-induced acute liver failure. DESIGN AND SETTING:A prospective observational study in two tertiary liver transplant units. PATIENTS:Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). MEASUREMENTS:Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed. MAIN RESULTS:Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755 (0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. CONCLUSIONS:Hepatocellular apoptosis occurs in the early phases of human acetaminophen-induced acute liver failure, peaking on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated levels of M30 are likely to reflect epithelial cell death in extrahepatic organs.

Project description:BackgroundAcute liver failure (ALF) is a life-threatening complication that is relatively uncommon. ALF causes severe hepatocyte damage and necrosis, which can lead to liver dysfunction and even multi-organ failure. A growing body of evidence suggests that immune cell infiltration and some abnormally expressed genes are associated with ALF development. However, in ALF, they have yet to be thoroughly investigated.MethodsThe Gene Expression Omnibus (GEO) database was used to obtain microarray datasets such as GSE74000, GSE120652, GSE38941, and GSE14668, which were then examined via GEO2R to determine differentially expressed genes (DEGs) associated with ALF. Metascape was employed to annotate the underlined genes using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The mechanism of IGF1 in 2 different kinds of ALF including acetaminophen-induced ALF and hepatitis B virus (HBV)-induced ALF was studied using gene set enrichment analysis (GSEA). Next, immune cell infiltration was investigated and differentiated in ALF using CIBERSORT.ResultsSix genes (HAO2, IGF1, PLA2G7, SC5D, GNE, SLC1A1) were found to be abnormally expressed in the 2 distinct types of ALF i.e., acetaminophen-induced ALF and HBV-induced ALF. IGF1 was identified as a hub gene in ALF and was found to be associated with several developmental cascades including immune responses, inflammatory responses, and intracellular calcium homeostasis. Additionally, the number of CD4 naive T cells, CD8 T cells, and follicular helper T cells was increased in acetaminophen-induced ALF, whereas the number of activated NK cells, resting NK cells, and plasma cells was increased in HBV-induced ALF.ConclusionsThe present study determined a potential molecular target, namely IGF1, in acetaminophen-induced ALF and HBV-induced ALF, which may provide novel insights into the pathophysiology and management of ALF. Concurrently, the putative immunological pathways have been found.

Dataset Information

Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure.

Publications

Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets