当前位置： SCI文献检索 > ARCHIVES OF TOXICOLOGY期刊下所有文献 > CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver.

CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver.

Abstract：

:Overdose of acetaminophen (APAP) causes necrosis of centrilobular cells of the liver. Accumulating evidence suggests that innate immune system may contribute to APAP-induced hepatotoxicity. Interaction between RANTES and its receptor C-C chemokine receptor (CCR) 5 is related to recruitment of macrophages to sites of inflammation. In this study, we examined effects of CCR5 deficiency on APAP-mediated liver injury by employing CCR5 knockout (KO) mice. CCR5 wild-type (WT) and KO mice received intraperitoneal injection of APAP (300 mg/kg) and were killed 24 h after the injection. Hepatic injury was determined by using histological and biochemical analyses. Intraperitoneal APAP caused the hepatocytic necrosis, as evidenced by hematoxylin and eosin staining and an increase in alanine transaminase and aspartate transaminase levels in serum. Hepatic damage appeared to be larger in CCR5 WT animals compared with KO animals. There were no differences in cytochrome P450 2E1 between CCR5 WT and KO animals suggesting that the resistance of CCR5 KO mice did not come from alterations in APAP metabolism. Infiltration of macrophages into the liver was reduced in CCR5 KO mice, and this was accompanied decreased inflammatory responses. Inhibition of macrophage activity by pretreatment of gadolinium chloride significantly blocked APAP-caused hepatotoxicity. These results indicate that recruitment of macrophage into the inflammatory sites significantly contributes to APAP-mediated hepatocytic death and CCR5 gene deletion protects from APAP-induced liver injury by alleviating macrophage recruitment and inflammatory responses. This study represents a critical role of CCR5 in macrophage infiltration into the liver and subsequent hepatotoxicity upon challenge of APAP.

journal_name

Arch Toxicol

journal_title

Archives of toxicology

authors

Choi DY,Ban JO,Kim SC,Hong JT

doi

10.1007/s00204-014-1253-3

subject

Has Abstract

pub_date

2015-02-01 00:00:00

pages

211-20

issue

eissn

0340-5761

issn

1432-0738

journal_volume

pub_type

杂志文章

在线工具

CCR5 knockout mice with C57BL6 background are resistant to acetaminophen-mediated hepatotoxicity due to decreased macrophages migration into the liver.