安普克
磷酸化
血红素加氧酶
内分泌学
医学
内科学
AMP活化蛋白激酶
蛋白激酶A
化学
肺
激酶
激活剂(遗传学)
生物
血红素
生物化学
酶
受体
作者
Israr Ahmad,Adam Molyvdas,Ming Jian,Ting Zhou,Amie M. Traylor,Huachun Cui,Gang Liu,Weifeng Song,Anupam Agarwal,Tamás Jilling,Saurabh Aggarwal,Sadis Matalon
出处
期刊:The European respiratory journal
[European Respiratory Society]
日期:2021-05-28
卷期号:58 (6): 2003694-2003694
被引量:20
标识
DOI:10.1183/13993003.03694-2020
摘要
We investigated the mechanisms by which N1-(β-d-ribofuranosyl)-5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase (AMPK), decreases lung injury and mortality when administered to mice post exposure to bromine gas (Br2).We exposed male C57BL/6 mice and heme oxygenase-1 (HO-1)-deficient (HO-1-/-) and corresponding wild-type (WT) littermate mice to Br2 (600 ppm for 45 or 30 min, respectively) in environmental chambers and returned them to room air. AICAR was administered 6 h post exposure (10 mg·kg-1, intraperitoneal). We assessed survival, indices of lung injury, high mobility group box 1 (HMGB1) in the plasma, HO-1 levels in lung tissues and phosphorylation of AMPK and its upstream liver kinase B1 (LKB1). Rat alveolar type II epithelial (L2) cells and human club-like epithelial (H441) cells were also exposed to Br2 (100 ppm for 10 min). After 24 h we measured apoptosis and necrosis, AMPK and LKB1 phosphorylation, and HO-1 expression.There was a marked downregulation of phosphorylated AMPK and LKB1 in lung tissues and in L2 and H441 cells post exposure. AICAR increased survival in C57BL/6 but not in HO-1-/- mice. In WT mice, AICAR decreased lung injury and restored phosphorylated AMPK and phosphorylated LKB1 to control levels and increased HO-1 levels in both lung tissues and cells exposed to Br2. Treatment of L2 and H441 cells with small interfering RNAs against nuclear factor erythroid 2-related factor 2 or HO-1 abrogated the protective effects of AICAR.Our data indicate that the primary mechanism for the protective action of AICAR in toxic gas injury is the upregulation of lung HO-1 levels.
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