BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils.
BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils.
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DOI：
10.1038/srep29650
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发表时间：
2016-07-11
影响因子：
4.6
通讯作者：
Majima M
中科院分区：
文献类型：
--
作者：
Kojo K;Ito Y;Eshima K;Nishizawa N;Ohkubo H;Yokomizo T;Shimizu T;Watanabe M;Majima M
白三烯B4（LTB 4）是一种有效的中性粒细胞化学引诱剂。LTB 4受体1型（BLT 1）的信号传导通过中性粒细胞募集具有促炎功能。在这项研究中，我们研究了BLT 1信号传导是否通过影响炎症反应（包括肝中性粒细胞的积累）在对乙酰氨基酚（APAP）诱导的肝损伤中发挥作用。对BLT 1基因敲除（BLT 1 −/−）小鼠及其野生型（WT）小鼠进行单次APAP过量（300 mg/kg）给药，并在给药后24小时内比较各种参数。与WT小鼠相比，BLT 1 −/−小鼠表现出APAP诱导的肝损伤加重，表现为丙氨酸氨基转移酶水平、坏死面积、肝中性粒细胞蓄积以及细胞因子和趋化因子表达的增加。用APAP和ONO-0457（一种BLT 1的特异性拮抗剂）共处理的WT小鼠显示出损伤的放大，并且与在BLT 1 −/−小鼠中观察到的结果相似。在APAP肝毒性期间，BLT 1 −/−小鼠的肝中性粒细胞显示活性氧和基质金属蛋白酶-9的产生增加。将分离的BLT 1缺陷型中性粒细胞给予WT小鼠加重了APAP引起的肝损伤。这些结果表明，BLT 1信号转导通过抑制活化的中性粒细胞的过度积累来抑制APAP肝毒性的进展。BLT 1特异性激动剂的开发可能有助于预防APAP肝毒性。
Leukotriene B4 (LTB4) is a potent chemoattractant for neutrophils. Signalling of LTB4 receptor type 1 (BLT1) has pro-inflammatory functions through neutrophil recruitment. In this study, we investigated whether BLT1 signalling plays a role in acetaminophen (APAP)-induced liver injury by affecting inflammatory responses including the accumulation of hepatic neutrophils. BLT1-knockout (BLT1−/−) mice and their wild-type (WT) counterparts were subjected to a single APAP overdose (300 mg/kg), and various parameters compared within 24 h after treatment. Compared with WT mice, BLT1−/− mice exhibited exacerbation of APAP-induced liver injury as evidenced by enhancement of alanine aminotransferase level, necrotic area, hepatic neutrophil accumulation, and expression of cytokines and chemokines. WT mice co-treated with APAP and ONO-0457, a specific antagonist for BLT1, displayed amplification of the injury, and similar results to those observed in BLT1−/− mice. Hepatic neutrophils in BLT1−/− mice during APAP hepatotoxicity showed increases in the production of reactive oxygen species and matrix metalloproteinase-9. Administration of isolated BLT1-deficient neutrophils into WT mice aggravated the liver injury elicited by APAP. These results demonstrate that BLT1 signalling dampens the progression of APAP hepatotoxicity through inhibiting an excessive accumulation of activated neutrophils. The development of a specific agonist for BLT1 could be useful for the prevention of APAP hepatotoxicity.