Alda-1 Attenuates Hyperoxia-Induced Acute Lung Injury in Mice

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.

Pharmacological Activation Of Aldehyde Dehydrogenase 2 Protects Against Heatstroke-Induced Acute Lung Injury by Modulating Oxidative Stress and Endothelial Dysfunction

“…Consistent with previous studies ( 14 , 17 ), We have found that there were increased total cells in the BALF in mice subjected to HS. A recent study regarding hyperoxia induced ALI also revealed that pretreatment with Alda-1 reduced hyperoxia induced immune cell infiltration, alveolar damage and lung inflammation and preserved alveolar permeability through the activation of Akt and mTOR pathways ( 35 ). Here we demonstrated that pretreatment with Alda-1 prevented HS-induced ALI by reducing ROS production, toxic aldehydes and mitochondrial injury and preserving the viability of ECs.…”

“…Previous studies indicated that Alda-1 attenuated the formation of 4-HNE protein adducts and inactivated the NF-κB pathway in several disease models ( 30 – 34 ). Pretreatment with Alda-1 had been shown to have beneficial effects on hyperoxia and acrolein induced ALI through preserving the endothelial barrier and mitochondrial dysfunction ( 35 – 37 ).…”

BMI1 Silencing Induces Mitochondrial Dysfunction in Lung Epithelial Cells Exposed to Hyperoxia

“…An additive effect was observed between BMI1 silencing and an increase in oxygen concentration, p = 0.016 for O 2 *siRNA ( Figures 2A,B and Table 1 ), evidenced by the decrease in the expression of DRP1 when BMI1 was silenced in H441 cells and exposed to HO. Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial protein involved in the oxidative metabolism of alcohol and a potential shield against oxidative stress ( Sidramagowda Patil et al, 2021 ), showed no significant changes following BMI1 silencing.…”

HINT1 Is Involved in the Chronic Mild Stress Elicited Oxidative Stress and Apoptosis Through the PKC ε/ALDH-2/4HNE Pathway in Prefrontal Cortex of Rats

“…Intriguingly, phosphorylation of PKC ε was proposed as an upstream regulatory molecule of ALDH2 alleviating OS and neuronal apoptosis ( Zuo et al, 2019 ). 4-HNE is a stable product of lipid peroxidation that acts as a key mediator of OS-induced cytotoxic effects, while ALDH2 serves as an endogenous shield against OS-mediated damage by clearing 4-HNE ( Sidramagowda Patil et al, 2020 ). Correspondingly, in this study, we found in PFC of CMS rats, high expression of HINT1 was accompanied with reduced expression of p- PKC ε and ALDH-2, while 4HNE was over-accumulated.…”