AICAR decreases acute lung injury by phosphorylating AMPK and upregulating heme oxygenase-1.
Eur Respir J
; 58(6)2021 12.
Article
em En
| MEDLINE
| ID: mdl-34049949
ABSTRACT
AIM:
We investigated the mechanisms by which N1-(ß-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 (600â ppm for 45 or 30â min, respectively) in environmental chambers and returned them to room air. AICAR was administered 6â h post exposure (10â 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 (100â ppm for 10â min). After 24â 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lesão Pulmonar Aguda
/
Proteínas Quinases Ativadas por AMP
Limite:
Animals
Idioma:
En
Revista:
Eur Respir J
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos