期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 428, 期 2, 页码 245-251出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2012.10.029
关键词
Glutathione; APAP; V alpha 14iNKT cells; ROS; Liver
资金
- NIH [NIAID R56A1085150, NIDDK DK44510]
Acetaminophen (APAP) overdose is widely regarded as a major cause of acute liver failure in the United States. Intentional Or accidental overdose of APAP in man or rodent elicits direct hepatocellular injury that is accompanied by hepatic depletion of the antioxidant, glutathione (GSH). In recent years, the innate immune response has also been shown to promote the development of APAP hepatotoxicity via indirect liver damage. In the present study, we demonstrate that J alpha 18(-/-) mice, which are selectively deficient in the innate immune T cell, V alpha 14iNKT cells, were resistant to APAP hepatotoxicity relative to WT mice as reflected by biochemical and histological liver injury markers. In parallel, improvement in the biochemical and histological parameters of liver injury in Ja18-/- mice was associated with a significant increase in hepatic levels of GSH, which detoxified APAP metabolites to attenuate hepatic oxidative stress, liver injury and necrosis. Notably, the protective effect of hepatic GSH during V alpha 14iNKT cells deficiency was demonstrated by its depletion in J alpha 18(-/-) mice using or-buthionine-[S,R]-sulfoximine which exacerbated hepatic oxidative and nitrosative stress as well as liver necrosis and caused mice mortality. Extraordinarily, APAP metabolism in J alpha 18(-/-) mice was altered in favor of hepatic GSH conjugates and decreased glucuronide conjugates. In summary, we reveal a novel finding establishing a unique association between hepatic innate immunity and GSH levels in altering APAP metabolism to suppress liver injury and necrosis during V alpha 14iNKT cells deficiency in J alpha 18(-/-) mice. (C) 2012 Elsevier Inc. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据