Toxicological Sciences 54, 509-516 (2000)
Copyright © 2000 by the Society of Toxicology
The Hepatic Inflammatory Response after Acetaminophen Overdose: Role of Neutrophils
>,1
* Department of Pharmacology, Pharmacia & Upjohn, Inc., Kalamazoo, Michigan 49007;
Department of Pathology, University of Texas Health Science Center, Houston, Texas 77030; and
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205
Acetaminophen overdose induces severe liver injury and hepatic failure. There is evidence that inflammatory cells may be involved in the pathophysiology. Thus, the aim of this investigation was to characterize the neutrophilic inflammatory response after treatment of C3Heb/FeJ mice with 300 mg/kg acetaminophen. A time course study showed that neutrophils accumulate in the liver parallel to or slightly after the development of liver injury. The number of neutrophils in the liver was substantial (209 ± 64 PMN/50 high-power fields at 12 h) compared to baseline levels (7 ± 1). Serum levels of TNF-
and the C-X-C chemokines KC and MIP-2 increased by 28-, 14-, and 295-fold, respectively, over levels found in controls during the injury process. In addition, mRNA expression of MIP-2 and KC were upregulated in livers of acetaminophen-treated animals as determined by ribonuclease protection assay. However, none of these mediators were generated in large enough quantities to account for neutrophil sequestration in the liver. There was no upregulation of Mac-1 (CD11b/CD18) or shedding of L-selectin on circulating neutrophils. Moreover, an anti-CD18 antibody had no protective effect against acetaminophen overdose during the first 24 h. These results indicate that there is a local inflammatory response after acetaminophen overdose, including a substantial accumulation of neutrophils in the liver. Because of the critical importance of ß2 integrins for neutrophil cytotoxicity, these results suggest that neutrophils do not contribute to the initiation or progression of AAP-induced liver. The inflammation observed after acetaminophen overdose may be characteristic for a response sufficient to recruit neutrophils for the purpose of removing necrotic cells but is not severe enough to cause additional damage.
Key Words: cytokines; chemokines; adhesion molecules; inflammation, liver necrosis; Mac-1 (CD11b/CD18); L-selectin (CD62L).
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