期刊
LIVER INTERNATIONAL
卷 32, 期 1, 页码 8-20出版社
WILEY
DOI: 10.1111/j.1478-3231.2011.02501.x
关键词
acetaminophen; hepatotoxicity; inflammation
资金
- National Institutes of Health [R01 DK070195, R01 AA12916]
- National Center for Research Resources (NCRR), National Institutes of Health [P20 RR016475, P20 RR021940]
- National Institute of Environmental Health Sciences [T32 ES007079-26A2]
- NATIONAL CENTER FOR RESEARCH RESOURCES [P20RR021940, P20RR016475] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK070195] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [T32ES007079] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P20GM103549] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA012916] Funding Source: NIH RePORTER
Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure in the western world. Metabolic activation of APAP and protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation and nuclear DNA fragmentation are critical intracellular events in hepatocytes. However, the early cell necrosis causes the release of a number of mediators such as high-mobility group box 1 protein, DNA fragments, heat shock proteins (HSPs) and others (collectively named damage-associated molecular patterns), which can be recognized by toll-like receptors on macrophages, and leads to their activation with cytokine and chemokine formation. Although pro-inflammatory mediators recruit inflammatory cells (neutrophils, monocytes) into the liver, neither the infiltrating cells nor the activated resident macrophages cause any direct cytotoxicity. In contrast, pro- and anti-inflammatory cytokines and chemokines can directly promote intracellular injury mechanisms by inducing nitric oxide synthase or inhibit cell death mechanisms by the expression of acute-phase proteins (HSPs, heme oxygenase-1) and promote hepatocyte proliferation. In addition, the newly recruited macrophages (M2) and potentially neutrophils are involved in the removal of necrotic cell debris in preparation for tissue repair and resolution of the inflammatory response. Thus, as discussed in detail in this review, the preponderance of experimental evidence suggests that the extensive sterile inflammatory response during APAP hepatotoxicity is predominantly beneficial by limiting the formation and the impact of pro-inflammatory mediators and by promoting tissue repair.
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