Inflammation In Hepatotoxicity Research Articles

IV009 Neutrophil chemotaxis and activation by pathogen-associated molecular patterns: role of formylated peptides and of novel bacterial chemoattractants

By receiving portal venous blood, the liver is exposed to a high variety of antigens; hence, the liver has an active innate immune system. Inflammation in the liver in response to infectious and noninfectious antigens is mediated by foreign pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) that are recognized by pattern recognition receptors (PRRs) on immune cells and hepatocytes. Toll-like receptors are the most well-known class of PRRs. Whereas inflammation is a mechanism of defense in response to invasive pathogens, it contributes to liver injury in various hepatic disease processes. In the setting of exposure to hepatotoxicants, inflammation often plays a prominent role in exacerbation of liver damage and ensuing repair processes. Because hepatotoxicants are not antigens themselves that activate the immune system directly, inflammation in hepatotoxicity is mediated by the release of PAMPs and DAMPs, and activation of PRRs. Alcohol and acetaminophen toxicity are the two most commonly encountered etiologies of xenobiotic-induced hepatotoxicity. They lead to liver injury by two distinct pathways, which are exemplary for the role of inflammation in hepatotoxicity. Alcohol causes an increase in intestinal permeability, resulting in portal venous lipopolysaccharide, a prototypical PAMP, which causes PRR stimulation in the liver. Acetaminophen metabolism in hepatocytes results in mitochondrial damage and release of reactive oxygen species causing cell necrosis and DAMP release, which propagates inflammation and further cell destruction. This article will provide an overview of the roles of TLRs, PAMPs, and DAMPs in inflammatory responses to common hepatotoxicants.