Liver cell death induced by stresses such as ischemia‐reperfusion, cholestasis and drug toxicity can trigger a sterile inflammatory response with activation of innate immune cells through release of ...damage‐associated molecular patterns (DAMPs). A similar inflammatory response can be induced by pathogen‐associated molecular patterns (PAMPs) such as endotoxin. Both DAMPs and PAMPs activate through toll‐like receptors the resident macrophages (Kupffer cells) and recruit activated neutrophils and monocytes into the liver. Central to this inflammatory response is promotion of reactive oxygen species (ROS) formation by these phagocytes. ROS are the principal toxic mediators by which inflammatory cells kill their targets, e.g. bacteria during host defense but also hepatocytes and other liver cells. The mechanism of ROS‐induced cell killing during inflammation involves the promotion of mitochondrial dysfunction through an intracellular oxidant stress in hepatocytes leading mainly to oncotic necrosis and less apoptosis. The additional release of cell contents amplifies the inflammatory injury. However, an inflammatory oxidant stress insufficient to directly cause cell damage can induce transcription of stress defence genes including antioxidant genes. This preconditioning effect of ROS enhances the resistance against future inflammatory oxidant stress and promotes the initiation of tissue repair processes. Despite the substantial progress in our understanding of mechanisms of inflammatory liver injury during the last decade, more research is necessary to better understand the role of ROS in acute liver inflammation and to develop clinically applicable therapeutic strategies that selectively target the detrimental effects of oxidant stress without compromising the vital function of ROS in host defense.
Drug-induced liver injury is a rare but serious clinical problem. A number of drugs can cause severe liver injury and acute liver failure at therapeutic doses in a very limited number of patients ...(<1:10,000). This idiosyncratic drug-induced liver injury, which is currently not predictable in preclinical safety studies, appears to depend on individual susceptibility and the inability to adapt to the cellular stress caused by a particular drug. In striking contrast to idiosyncratic drug-induced liver injury, drugs with dose-dependent hepatotoxicity are mostly detected during preclinical studies and do not reach the market. One notable exception is acetaminophen (APAP, paracetamol), which is a safe drug at therapeutic doses but can cause severe liver injury and acute liver failure after intentional and unintentional overdoses. Key Messages: APAP overdose is responsible for more acute liver failure cases in the USA or UK than all other etiologies combined. Since APAP overdose in the mouse represents a model for the human pathophysiology, substantial progress has been made during the last decade in understanding the mechanisms of cell death, liver injury and recovery. More recently, emerging evidence based on mechanistic biomarker analysis in patients and studies of cell death in human hepatocytes suggests that most of the mechanisms discovered in mice also apply to patients. The rapid development of N-acetylcysteine as an antidote against APAP overdose was based on the early understanding of APAP toxicity in mice. However, despite the efficacy of N-acetylcysteine in patients who present early after APAP overdose, there is a need to develop intervention strategies for late-presenting patients.
The challenges related to APAP toxicity are to better understand the mechanisms of cell death in order to limit liver injury and prevent acute liver failure, and also to develop biomarkers that better predict as early as possible who is at risk for developing acute liver failure with poor outcome.
Polymorphonuclear leukocytes (neutrophils) are a vital part of the innate immune response to microbial infections and tissue trauma, e.g., ischemia-reperfusion injury, in many organs including the ...liver. However, an excessive inflammatory response can lead to a dramatic aggravation of the existing injury. To design interventions, which selectively target the detrimental effects of neutrophils, a detailed understanding of the pathophysiology is critical. Systemic or local exposure to proinflammatory mediators causes activation and priming of neutrophils for reactive oxygen formation and recruits them into the vascular beds of the liver without causing tissue injury. However, generation of a chemotactic signal from the parenchyma will trigger extravasation and an attack on target cells (e.g., hepatocytes). Adhesion to the target induces degranulation with release of proteases and formation of reactive oxygen species including hydrogen peroxide and hypochlorous acid, which can diffuse into hepatocytes and induce an intracellular oxidant stress and mitochondrial dysfunction. Various neutrophil-derived proteases are involved in transmigration and cell toxicity but can also promote the inflammatory response by processing of proinflammatory mediators. In addition, necrotic cells release mediators, e.g., high-mobility group box-1, which further promotes neutrophilic hepatitis and tissue damage. On the basis of these evolving insights into the mechanisms of neutrophil-mediated liver damage, the most selective strategies appear not to interfere with the cytotoxic potential of neutrophils, but rather strengthen the target cells' defense mechanisms including enhancement of the intracellular antioxidant defense systems, activation of cell survival pathways, or initiation of cell cycle activation and regeneration.
Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where ...it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.
Acetaminophen (APAP) is a widely used analgesic drug, which can cause severe liver injury after an overdose. The intracellular signaling mechanisms of APAP-induced cell death such as reactive ...metabolite formation, mitochondrial dysfunction and nuclear DNA fragmentation have been extensively studied. Hepatocyte necrosis releases damage-associated molecular patterns (DAMPs) which activate cytokine and chemokine formation in macrophages. These signals activate and recruit neutrophils, monocytes and other leukocytes into the liver. While this sterile inflammatory response removes necrotic cell debris and promotes tissue repair, the capability of leukocytes to also cause tissue injury makes this a controversial topic. This review summarizes the literature on the role of various DAMPs, cytokines and chemokines, and the pathophysiological function of Kupffer cells, neutrophils, monocytes and monocyte-derived macrophages, and NK and NKT cells during APAP hepatotoxicity. Careful evaluation of results and experimental designs of studies dealing with the inflammatory response after APAP toxicity provide very limited evidence for aggravation of liver injury but support of the hypothesis that these leukocytes promote tissue repair. In addition, many cytokines and chemokines modulate tissue injury by affecting the intracellular signaling events of cell death rather than toxicity of leukocytes. Reasons for the controversial results in this area are also discussed.
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 occurred recently in the literature over whether or not there exists a second phase of injury, mediated by inflammatory processes. Critical to this potential inflammatory process is the activation of caspase-1 and interleukin-1ß by a molecular complex known as the inflammasome. A number of different stimuli for formation of multiple different inflammasome complexes have been identified. Formation of the Nalp3 inflammasome in particular has directly been attributed to late-stage acetaminophen toxicity. In this review, we will discuss mechanisms of acetaminophen-induced liver injury in mice and man with a particular focus on the role of inflammation and the inflammasome.
ABSTRACT
Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first ...studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered.
Acetaminophen (APAP) hepatotoxicity is characterized by an extensive oxidative stress. However, its source, pathophysiological role and possible therapeutic potential if targeted, have been ...controversially described. Earlier studies argued for cytochrome P450-generated reactive oxygen species (ROS) during APAP metabolism, which resulted in massive lipid peroxidation and subsequent liver injury. However, subsequent studies convincingly challenged this assumption and the current paradigm suggests that mitochondria are the main source of ROS, which impair mitochondrial function and are responsible for cell signaling resulting in cell death. Although immune cells can be a source of ROS in other models, no reliable evidence exists to support a role for immune cell-derived ROS in APAP hepatotoxicity. Recent studies suggest that mitochondrial targeted antioxidants can be viable therapeutic agents against hepatotoxicity induced by APAP overdose, and re-purposing existing drugs to target oxidative stress and other concurrent signaling events can be a promising strategy to increase its potential application in patients with APAP overdose.
Ischemia-reperfusion injury is, at least in part, responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. The pathophysiology of ...hepatic ischemia-reperfusion includes a number of mechanisms that contribute to various degrees in the overall injury. Some of the topics discussed in this review include cellular mechanisms of injury, formation of pro- and anti-inflammatory mediators, expression of adhesion molecules, and the role of oxidant stress during the inflammatory response. Furthermore, the roles of nitric oxide in preventing microcirculatory disturbances and as a substrate for peroxynitrite formation are reviewed. In addition, emerging mechanisms of protection by ischemic preconditioning are discussed. On the basis of current knowledge, preconditioning or pharmacological interventions that mimic these effects have the greatest potential to improve clinical outcome in liver surgery involving ischemic stress and reperfusion.
PDF
