The hepatic inflammatory response after acetaminophen overdose: Role of neutrophils

Acetaminophen overdose induces severe liver injury and hepatic failure. The re is evidence that inflammatory cells may be involved in the pathophysiolo gy. Thus, the aim of this investigation was to characterize the neutrophili c inflammatory response after treatment of C3Heb/FeJ mice with 300 mg/kg ac etaminophen, A time course study showed that neutrophils accumulate in the liver parallel to or slightly after the development of liver injury. The nu mber of neutrophils in the liver was substantial (209 +/- 64 PMN/50 high-po wer fields at 12 h) compared to baseline levels (7 +/- 1). Serum levels of TNF-alpha 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 pro cess. In addition, mRNA expression of MIP-2 and KC were upregulated in live rs of acetaminophen-treated animals as determined by ribonuclease protectio n assay, However, none of these mediators were generated in large enough qu antities to account for neutrophil sequestration in the liver. There was no upregulation of Mac-1 (CD11b/ CD18) or shedding of L-selectin on circulati ng neutrophils, Moreover, an anti-CD18 antibody had no protective effect ag ainst acetaminophen overdose during the first 24 h, These results indicate that there is a local inflammatory response after acetaminophen overdose, i ncluding a substantial accumulation of neutrophils in the liver. Because of the critical importance of beta(2) 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 acetam inophen overdose may be characteristic for a response sufficient to recruit neutrophils for the purpose of removing necrotic cells but is not severe e nough to cause additional damage.