Alda-1 Protects Against Acrolein-Induced Acute Lung Injury and Endothelial Barrier Dysfunction

Abstract

Inhalation of acrolein, a highly reactive aldehyde, causes lung edema. The underlying mechanism is poorly understood and there is no effective treatment. In this study, we demonstrated that acrolein not only dose-dependently induced lung edema but also promoted LPS-induced acute lung injury. Importantly, acrolein-induced lung injury was prevented and rescued by Alda-1, an activator of mitochondrial aldehyde dehydrogenase 2. Acrolein also dose-dependently increased monolayer permeability, disrupted adherens junctions and focal adhesion complexes, and caused intercellular gap formation in primary cultured lung microvascular endothelial cells (LMVECs). These effects were attenuated by Alda-1 and the antioxidant N-acetylcysteine, but not by the NADPH inhibitor apocynin. Furthermore, acrolein inhibited AMP-activated protein kinase (AMPK) and increased mitochondrial reactive oxygen species levels in LMVECs-effects that were associated with impaired mitochondrial respiration. AMPK total protein levels were also reduced in lung tissue of mice and LMVECs exposed to acrolein. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside blunted an acrolein-induced increase in endothelial monolayer permeability, but not mitochondrial oxidative stress or inhibition of mitochondrial respiration. Our results suggest that acrolein-induced mitochondrial dysfunction may not contribute to endothelial barrier dysfunction. We speculate that detoxification of acrolein by Alda-1 and activation of AMPK may be novel approaches to prevent and treat acrolein-associated acute lung injury, which may occur after smoke inhalation.

Effects of cigarette smoke on pulmonary endothelial cells

“…It is likely that multiple components of cigarette smoke are responsible for increased endothelial permeability. We have demonstrated that acrolein increased endothelial monolayer and lung microvascular permeability in vivo (82). Schweitzer et al reported that nicotine, e-cigarette solution, and condensed e-cigarette vapor increased endothelial monolayer permeability (119).…”

“…Acrolein is of particular interest since increased levels have been found in blood and urine of smokers (7). Intraperitoneal administration of acrolein causes emphysema in rats (71), and intratracheal instillation increases lung vascular permeability in mice (82). A recent review summarized the known effects on lung function of nicotine administered by electronic cigarettes (30).…”

Cigarette smoke alters lung vascular permeability and endothelial barrier function (2017 Grover Conference Series)

“…Similar to smoke inhalation, acrolein inhalation has been shown to cause non-cardiogenic pulmonary edema and respiratory distress in sheep 36 , 37 and dogs 38 and perivascular cuffing in susceptible mouse strains. 39 We found that acrolein increases lung microvascular endothelial cell permeability in vitro and causes lung edema as well as exacerbating LPS-induced lung injury in mice, 40 similar to the effects of CS. We found that pretreatment of mice with Alda-1 (NC1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide), a selective ALDH2 activator, significantly attenuated acrolein-induced increase in BAL protein content ( Fig.…”

Co‐administration of N‐acetylcysteine and dexmedetomidine plays a synergistic effect on protection of LPS‐induced acute lung injury via correcting Th1/Th2/Th17 cytokines imbalance

“…N‐acetylcysteine (NAC) as an antioxidant can reduce reactive oxygen spices, free radical damage and produce an anti‐inflammatory effect . Increasing studies suggested NAC might be used in ALI protection for its antioxidant and anti‐inflammatory properties . However, ALI is a multifactorial disorder which not only involves in inflammation and oxidation but also involves in immune dysfunction.…”

“…3 Increasing studies suggested NAC might be used in ALI protection for its antioxidant and anti-inflammatory properties. 4,5 However, ALI is a multifactorial disorder which not only involves in inflammation and oxidation but also involves in immune dysfunction. Whether NAC can also modulate the aberrant immunity during ALI remains largely unknown.…”