Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

Abstract

Purpose of Review This article provides a brief overview of mechanisms of inflammatory liver injury and how this applies to drug hepatotoxicity with a particular emphasis on the role of inflammation in acetaminophen-induced liver injury. Recent Findings Significant progress has been made in the last decade in our understanding of the initiation of sterile inflammation after necrotic cell death by the release of damage-associated molecular patterns and their recognition by toll-like receptors and others on macrophages. These events trigger the formation of cytokines and chemokines directly or with assistance of inflammasome activation thereby activating and recruiting leukocytes including neutrophils and monocyte-derived macrophages into the necrotic areas. Although this sterile inflammatory response is mainly geared towards the removal of necrotic cell debris and preparation of regeneration, there are conditions where these innate immune cells can aggravate the initial injury. The mechanisms and controversial findings of the innate immunity are being discussed in detail. In contrast, drug metabolism and formation of a reactive metabolite that binds to proteins in the absence of extensive cell death, can induce an adaptive immune response, which eventually also results in severe liver injury. However, the initiating event appears to be the formation of protein adducts, which act as haptens to activate an adaptive immune response. Overall, these mechanisms are less well understood. Summary The past decade has revolutionized our understanding of the mechanisms that control the interplay between cell death and innate or adaptive immune responses. This report provides an update on these mechanisms.

Subchronic Systemic Toxicity of New Endodontic Material Based on Calcium Hydroxyapatite and Calcium Silicates

“…e morphometric analysis of the liver tissue pointed out the absence of a mild inflammatory reaction in the portal areas of liver in the control and experimental groups, which indicates that there was no significant damage to the liver [1,13,23,24]. Also, the absence of degenerative changes in the biliary ductal epithelium and the rare, mild, and moderate necrosis confirmed that ALBO-MPSA had very low and insignificant impact on the liver tissue [25][26][27]. Fatty changes in hepatocytes have not been observed.…”

“…Increased activity of the liver was also indicated by an increase in the number and density of the cells and a moderate increase in the liver sinusoids and hepatocyte surface [25,32]. In addition, the levels of AST, ALT, and ALP in the blood, which indicate liver damage, were not significantly different in the control and experimental groups, also indicating that there was no hepatocellular liver injury [24,26].…”

Cinnamon oil against acetaminophen-induced acute liver toxicity by attenuating inflammation, oxidative stress and apoptosis

“…APAP metabolites are also linked with lipid and nucleic acid leading to permeability perturbation and impaired cytoplasmic, serum indicators along with total protein. Serum levels of ALT, AST, ALP, serum bilirubin, albumin and total protein should serve as hepatotoxicity indexes [ 13 , 14 ]. The liver damaged by oxidative stress is also activated by reactive oxygen species which provoke inflammatory cytokines such as IL-1β and IL-6 which further worsens liver damage [ 14 ].…”

“…Serum levels of ALT, AST, ALP, serum bilirubin, albumin and total protein should serve as hepatotoxicity indexes [ 13 , 14 ]. The liver damaged by oxidative stress is also activated by reactive oxygen species which provoke inflammatory cytokines such as IL-1β and IL-6 which further worsens liver damage [ 14 ]. Oxidative stress and inflammation are well documented to have the foremost protagonist in APAP facilitated liver damage [ 15 , 16 ].…”

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“…When the liver is stimulated by external trauma or harmful substances, macrophages are firstly activated to play a role of immune defense for phagocytosis and remove the harmful substances to protect the liver. However, with the secretion of inflammatory factors, excessive or unsolvable inflammatory reaction is nearly always accompanied by a massive loss of hepatocytes, resulting in irreversible damage to the hepatic parenchyma [28,29]. TNF-α is part of the most important inflammatory factors.…”