Journal
EUROPEAN RESPIRATORY JOURNAL
Volume 58, Issue 6, Pages -Publisher
EUROPEAN RESPIRATORY SOC JOURNALS LTD
DOI: 10.1183/13993003.03694-2020
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Funding
- CounterACT Program, National Institutes of Health Office of the Director (NIH OD)
- National Institute of Neurological Disorders and Stroke (NINDS)
- National Institute of Environmental Health Sciences (NIEHS) [5UO1 ES026458, 3UO1 ES026458 03S1, 5UO1 ES027697, R21 NS090024]
- NIH/NIDDK [R01 DK059600, P30 DK079337]
- CFAR pilot funding [P30 AI027767-32]
- CCTS pilot funding [UL1TR003096]
- NIH/NHLBI [K12 HL143958]
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The study demonstrated that AICAR exerts protective effects in lung injury post exposure to bromine gas by upregulating lung HO-1 levels.
Aim We investigated the mechanisms by which N1-(beta-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). Methods 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 mgmiddotkg-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. Results 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. Conclusions 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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