Abstract
AimWe 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).
MethodsWe 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.
ResultsThere 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.
ConclusionsOur data indicate that the primary mechanism for the protective action of AICAR in toxic gas injury is the upregulation of lung HO-1 levels.
Abstract
Attenuated AMPK activity plays a critical role in the development of acute lung injury. Treatment with an AMP analogue, AICAR, mitigates lung injury by upregulating the antioxidant enzyme heme oxygenase-1.https://bit.ly/3eJrbgb
Footnotes
This article has an editorial commentary:https://doi.org/10.1183/13993003.02238-2021
Author contributions: I. Ahmad and A. Molyvdas contributed equally to this study. I. Ahmad, A. Molyvdas and M-Y. Jian designed the study, conducted experiments, analysed the data and wrote drafts of the manuscript; T. Zhou conducted experiments and analysed data; A.M. Traylor conducted experiments; H. Cui conducted experiments and analysed data; G. Liu contributed to experimental design, data analysis and interpretation; W. Song contributed to experimental design and conducted experiments; A. Agarwal contributed to experimental design, data interpretation and writing of the manuscript; T Jilling conducted experiments and contributed to experimental design; S. Aggarwal contributed to study design, data analysis and writing of the manuscript; S. Matalon designed the study, analysed the data and wrote the manuscript. S. Aggarwal and S. Matalon contributed equally as senior authors.
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Conflict of interest: I. Ahmad has nothing to disclose.
Conflict of interest: A. Molyvdas has nothing to disclose.
Conflict of interest: M-Y. Jian has nothing to disclose.
Conflict of interest: T. Zhou has nothing to disclose.
Conflict of interest: A.M. Traylor has nothing to disclose.
Conflict of interest: H. Cui has nothing to disclose.
Conflict of interest: G. Liu has nothing to disclose.
Conflict of interest: W. Song has nothing to disclose.
Conflict of interest: A. Agarwal reports other (advisory board) from Akebia Therapeutics and Reata Pharmaceuticals, grants and other (advisory board) from Angion, and other (advisory board and stock options) from Goldilocks Therapeutics, outside the submitted work.
Conflict of interest: T. Jilling has nothing to disclose.
Conflict of interest: S. Aggarwal has nothing to disclose.
Conflict of interest: S. Matalon has nothing to disclose.
Support statement: This work was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Environmental Health Sciences (NIEHS), grant numbers 5UO1 ES026458, 3UO1 ES026458 03S1 and 5UO1 ES027697 (to S. Matalon); R21 NS090024 (to S. Matalon and A. Agarwal); NIH/NIDDK R01 DK059600 (to A. Agarwal); NIH/NIDDK P30 DK079337 (to A. Agarwal); CFAR pilot funding P30 AI027767-32 (to S. Aggarwal), CCTS pilot funding UL1TR003096 (to S. Aggarwal); NIH/NHLBI K12 HL143958 (to S. Aggarwal). Funding information for this article has been deposited with theCrossref Funder Registry.
- ReceivedSeptember 30, 2020.
- AcceptedMay 11, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contactpermissions{at}ersnet.org