Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity

• Published in: Current pharmacology reports 2018-10, Vol.4 (5), p.346-357
• Main Authors: Woolbright, Benjamin L., Jaeschke, Hartmut
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Cancer Research; Drug-induced Liver Injury (X Ma; Molecular Medicine; Pharmacology/Toxicology; Section Editor; Topical Collection on Drug-induced Liver Injury
• ISSN: 2198-641X; 2198-641X
• DOI: 10.1007/s40495-018-0147-0

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.