Decoding cell death signals in liver inflammation.

By C. Brenner, L. Galluzzi, Oliver Kepp, Guido Kroemer. Journal of Hepatology, 2013

961 citations recorded by the source corpus.

Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including - but not limited to - cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes.

Subfields: Epidemiology, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/e748440ce0b6d071c9cd3c8fe707d3b99215c983

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Citations in the corpus

Caspases in cell death, inflammation and disease (2019, background): “Extensive apoptosis also contributes to hepatocellular pathology in a mouse model of anti-Fas antibody-induced fulminant hepatitis by inducing activation of caspase-8 and truncated Bid-mediated activation of caspase-9 (Brenner et al., 2013).”
Inflammatory responses and inflammation-associated diseases in organs (2015, background): “Inflammation in the liver protects this organ from infection and injury, but excessive inflammation may lead to extensive loss of hepatocytes, ischemia-reperfusion injury, metabolic alterations, and eventually permanent hepatic damage [128].”
Hepatic stellate cells as key target in liver fibrosis (2017, background): “nucleotides can contribute to initiation of HSC activation [8,41,42].”
Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “…of adaptation as well as upon the permeabilization of the plasma membrane (an inevitable consequence of cell death) (Galluzzi et al., 2015), cells emit several signals (in the form of soluble or plasmamembraneassociated molecules) that alert the organism of a potential harm (Brenner et al., 2013).”
Nrf2, the Master Regulator of Anti-Oxidative Responses (2017, background): “The liver, as the main organ for biotransformation and subsequent detoxification of xenobiotics, has a high metabolic rate and is, therefore, prone to chemical and oxidative stress [70].”
Current and future pharmacological therapies for NAFLD/NASH (2017, background): “Selonsertib Apoptosis signal-regulating kinase 1 (ASK1) is activated by extracellular TNFa, intracellular oxidative or ER stress and initiates the p38/JNK pathway, resulting in apoptosis and fibrosis [70].”