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.

我们研究了 N1-(β-d-呋喃核糖基)-5-氨基咪唑-4-甲酰胺核糖核苷酸 (AICAR)（一种 AMP 活化蛋白激酶 (AMPK) 的激活剂）在对小鼠给药后降低肺损伤和死亡率的机制。暴露于溴气 (Br ₂ )。

我们将雄性 C57BL/6 小鼠和血红素加氧酶-1 (HO-1) 缺陷型 (HO-1 ^–/– ) 和相应的野生型 (WT) 同窝小鼠暴露于 Br ₂ (600 ppm 分别为 45 或 30 分钟) ) 在环境室中并将它们返回到室内空气中。AICAR 在暴露后 6 小时给药（10 mg·kg ^–1，腹膜内）。我们评估了存活率、肺损伤指数、血浆中的高迁移率组框 1 (HMGB1)、肺组织中的 HO-1 水平以及 AMPK 及其上游肝激酶 B1 (LKB1) 的磷酸化。大鼠肺泡 II 型上皮 (L2) 细胞和人类棒状上皮 (H441) 细胞也暴露于 Br ₂ (100 ppm 10 分钟)。24 小时后，我们测量了细胞凋亡和坏死、AMPK 和 LKB1 磷酸化以及 HO-1 表达。

暴露后肺组织和 L2 和 H441 细胞中磷酸化的 AMPK 和 LKB1 显着下调。AICAR 在 C57BL/6 中提高了存活率，但在 HO-1 ^–/–小鼠中没有。_{在 WT 小鼠中，AICAR 减少肺损伤并恢复磷酸化 AMPK 和磷酸化 LKB1 以控制水平，并增加暴露于 Br 2}的肺组织和细胞中的 HO-1 水平。用针对核因子红细胞 2 相关因子 2 或 HO-1 的小干扰 RNA 处理 L2 和 H441 细胞消除了 AICAR 的保护作用。

我们的数据表明，AICAR 在有毒气体损伤中的保护作用的主要机制是上调肺 HO-1 水平。