AMPK Activation Improves Survivability after Toxic Gas Exposure
Authors: Ahmad Israr , Zhou Ting , Jian Ming Yuan , Doran Stephen F , Wolkowicz Paul , Aggarwal Saurabh , Creighton Judy , Matalon Sadis 
Published: June 2021

Introduction

Inhalation injury caused by irritant gases such as smoke, ozone, chlorine and bromine (Br2) results in an environmental and occupational hazards that leads to reactive airway disease syndrome (RADS), acute lung injury (ALI), and even death from respiratory failure. Development of interventional therapeutic agents, which when given post exposure, prevent acute inhalation injury and decrease mortality are urgently needed. AMP‐activated protein kinase (AMPK) is a metabolic sensor that maintains cellular ATP levels during metabolic stress. AMPK also acts independently of AMP and enhances vascular integrity by preventing actin stress fiber formation and limiting changes in cell morphology necessary for increased endothelial permeability. Here in the current study we tested the hypothesis that a single injection of an AMPK activator, such as 5‐aminoimidazole‐4‐carboxamide‐1‐beta‐D‐ribofuranoside (AICAR), administered intraperitoneally to C57BL/6 mice, post exposure to a lethal dose of inhaled Br2, decreases lung injury and mortality.

Methods

C57BL/6 mice were exposed to Br2 (600 ppm, 45min) in environmental glass chambers and then returned to room air. Control mice breathed ambient air throughout this protocol. Six hours after exposure to Br2, mice were treated with either AICAR (10 mg/kg BW, intraperitoneally) or vehicle (Earle's balanced salt solution. Next seven days mice were monitored at interval of six hours. In another set of experiments, mice were sacrificed 24 hours post Br2 inhalation and were either lavaged with one ml of normal saline for protein and inflammatory cell counts or their lungs were fixed by instillation of formalin at 25 cm H20; and processed for histology.

Results

The analysis of the Kaplan Meier survival curve showed that Br2 exposed mice developed progressive respiratory distress. Median survival after Br2 exposure was one day. However, mice receiving AICAR had a median survival of six days. Exposure to Br2 caused significant increase in total protein and number of inflammatory cells in BALF at 24 hours post exposure, consistent with severe injury to the blood gas barrier. AICAR returned these values to their corresponding air controls. Br2 exposure significantly reduced the level of AMPK phosphorylation whereas AICAR treatment brought its level to normal in animal lungs. Lung H&E staining showed that AICAR attenuated Br2‐induced lung edema, alveolar congestion, septal thickening, neutrophil infiltration, hyaline membrane and perivascular cuffing. Results also showed that AICAR enhanced autophagy, which was significantly reduced after Br2 exposure suggesting a possible mechanism of AICAR‐mediated cyto‐protection.

Conclusions

In conclusion data suggest that activation of lung AMPK might be a useful target for a therapeutic intervention to reverse Br2‐induced acute lung injury.

Support or Funding Information

This study was supported by 1U01ES027697‐01 and 5U01ES026458‐02 to S. Matalon.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.