Abstract
Acute lung injury (ALI), a milder form of acute respiratory distress syndrome (ARDS), is a leading cause of mortality in older adults with an increasing prevalence. Oxygen therapy, is a common treatment for ALI, involving exposure to a high concentration of oxygen. Unfortunately, hyperoxia induces the formation of reactive oxygen species which can cause an increase in 4-HNE (4-hydroxy 2 nonenal), a toxic byproduct of lipid peroxidation. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) serves as an endogenous shield against oxidative stress-mediated damage by clearing 4-HNE. Alda-1 [(N-(1, 3 benzodioxol-5-ylmethyl)-2, 6- dichloro-benzamide)], a small molecular activator of ALDH2, protects against reactive oxygen species-mediated oxidative stress by promoting ALDH2 activity. As a result, Alda-1 shields against ischemic reperfusion injury, heart failure, stroke, and myocardial infarction. However, the mechanisms of Alda-1 in hyperoxia-induced ALI remains unclear. C57BL/6 mice implanted with Alzet pumps received Alda-1 in a sustained fashion while being exposed to hyperoxia for 48 h. The mice displayed suppressed immune cell infiltration, decreased protein leakage and alveolar permeability compared to controls. Mechanistic analysis shows that mice pretreated with Alda-1 also experience decreased oxidative stress and enhanced levels of p-Akt and mTOR pathway associated proteins. These results show that continuous delivery of Alda-1 protects against hyperoxia-induced lung injury in mice.
Highlights
There are more than 200,000 annual cases of acute lung injury (ALI) in the United States with a mortality rate of 40–50% (Rubenfeld et al, 2005; Galam et al, 2015)
This study evaluated the protective role of Alda-1 in Hyperoxia induced acute lung injury (HALI) murine model for the first time
In other studies Alda-1 was administered intraperitoneally (Zhu et al, 2017; Hua et al, 2019)and in this study Alda-1 administration was via Alzet pumps in a sustained fashion due to the short half-life and this pretreatment was continued throughout the hyperoxia exposure for 48 h (Zambelli et al, 2014)
Summary
There are more than 200,000 annual cases of acute lung injury (ALI) in the United States with a mortality rate of 40–50% (Rubenfeld et al, 2005; Galam et al, 2015). ALI patients commonly use oxygen therapy as a treatment; high concentrations of oxygen can exacerbate the condition and cause further alveolar injury (Galam et al, 2015). Hyperoxia induces ALI in small animal and primate models (Fukumoto et al, 2013; Kallet and Matthay, 2013). It promotes inflammation and causes infiltration of cytokines, macrophages, and neutrophils, and results in edema, alveolar.
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