Abstract
Severe hemorrhagic shock and resuscitation (HS/R) can lead to lung injury, resulting in respiratory insufficiency. We investigated whether treatment with Alda-1, an ALDH2 activator, decreased lung injury induced by severe HS/R in a rat model. Male Sprague-Dawley rats were randomized into three groups, hemorrhagic shock + placebo, hemorrhagic shock + Alda-1, and sham. All animals were heparinized, and then 50% of the total calculated blood volume was collected over 60 minutes. After 40 minutes of hemorrhagic shock, animals were reinfused with the shed blood over 40 minutes and then observed for an additional 2 hours. Concentrations of 4-HNE, TNF-α, IL-6, and ALDH2 activity were detected; lung injury and lung wet-to-dry weight ratios were assessed. Expression of occludin and ZO-1 proteins in lung tissues was also determined. At 2 hours after resuscitation, lung injury was significantly reduced and the wet-to-dry weight ratio was notably decreased in the Alda-1 group compared with placebo (P<0.05). Alda-1 treatment also significantly increased the activity of ALDH2 and decreased the levels of toxic 4-HNE (P<0.05). In the Alda-1 group, IL-6 and TNF-α were dramatically decreased compared with placebo-treated animals (P<0.05). Expression of occludin and ZO-1 proteins was significantly decreased in the placebo group compared with the Alda-1 group (P<0.05). Thus, in a rat model of severe HS/R, treatment with Alda-1 increased the activity of ALDH2, significantly accelerated the clearance of reactive aldehydes, and concomitantly alleviated lung injury through improvement of pulmonary epithelial barrier integrity resulting in decreased alveolar epithelial tissue permeability, lung edema, and diffuse infiltration of inflammatory cells.
Highlights
Hemorrhage accounts for up to approximately 40% of trauma-related deaths
Besides its role in early mortality, it is known that severe hemorrhagic shock and resuscitation (HS/R) can result in oxidative stress, which contributes to the development of organ injury, especially in the lungs [1]
During the hemorrhage and shock phases, the mean arterial pressure (MAP) was significantly decreased in both HS/R groups when compared with the sham group
Summary
Besides its role in early mortality, it is known that severe hemorrhagic shock and resuscitation (HS/R) can result in oxidative stress, which contributes to the development of organ injury, especially in the lungs [1]. ROS-induced oxidative stress injury can be amplified and propagated by toxic aldehydes produced by ROS-triggered peroxidation of unsaturated lipids [7]. Toxic aldehydes, such as 4-hydroxynonenal (4-HNE), are more stable than ROS, further exacerbating pulmonary injury and enhancing the intense inflammatory response. Detoxification of reactive aldehydes is an endogenous protective mechanism
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