AICAR decreases acute lung injury by phosphorylating AMPK and upregulating heme oxygenase-1.

Introduction Herein we investigated the mechanisms by which 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of adenosine monophosphate (AMP)-activated protein kinase (AMPK), administered to mice post exposure to bromine (Br2), decreases lung injury and mortality. Methods We exposed male C57BL/6 mice as well as heme oxygenase-1 deficient (HO-1−/−) and corresponding WT littermate mice to Br2 (600 ppm for 45 or 30 min respectively) gas in environmental chambers and returned them to room air. AICAR was administered 6 h post-exposure (10 mg·kg−1, IP). 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 lung Type II epithelial cells (L2) and human club-like epithelial cells (H441) were also exposed to Br2 (100 ppm for 10 min). Twenty-four h later we measured apoptosis and necrosis, AMPK and LKB1 phosphorylation and HO-1 expression. Results There was a marked downregulation of phosphorylated AMPK and LKB1 in both lung tissues and L2 and H441 cells post-exposure. AICAR increased survival in C57BL/6 but not in HO-1−/− mice. Additionally, in WT mice AICAR decreased lung injury and restored pAMPK and pLKB1 to control levels and increased HO-1 levels in both lung tissues and cells exposed to Br2. Treatment of L2 and H441 cells with siRNAs against Nrf2 or HO-1 abrogated the protective effects of AICAR. Conclusions Our data indicate that the primary mechanism for the protective action of AICAR in toxic gas injury is by upregulating lung HO-1 levels.