Abstract
Prolonged exposure to oxidative stress causes Acute Lung Injury (ALI) and significantly impairs pulmonary function. Previously we have demonstrated that mitochondrial dysfunction is a key pathological factor in hyperoxic ALI. While it is known that hyperoxia induces the production of stable, but toxic 4-hydroxynonenal (4-HNE) molecule, it is unknown how the reactive aldehyde disrupts mitochondrial function. Our previous in vivo study indicated that exposure to hyperoxia significantly increases 4-HNE-Protein adducts, as well as levels of MDA in total lung homogenates. Based on the in vivo studies, we explored the effects of 4-HNE in human small airway epithelial cells (SAECs). Human SAECs treated with 25 μM of 4-HNE showed a significant decrease in cellular viability and increased caspase-3 activity. Moreover, 4-HNE treated SAECs showed impaired mitochondrial function and energy production indicated by reduced ATP levels, mitochondrial membrane potential, and aconitase activity. This was followed by a significant decrease in mitochondrial oxygen consumption and depletion of the reserve capacity. The direct effect of 4-HNE on the mitochondrial respiratory chain was confirmed using Rotenone. Furthermore, SAECs treated with 25 μM 4-HNE showed a time-dependent depletion of total Thioredoxin (Trx) proteins and Trx activity. Taken together, our results indicate that 4-HNE induces cellular and mitochondrial dysfunction in human SAECs, leading to an impaired endogenous antioxidant response.
Highlights
Hyperoxic acute lung injury (HALI) triggers cellular damage and produces reactive oxygen species (ROS) that interfere with the cell’s intrinsic antioxidant responses [1,2,3]
Our results indicate that 4-HNE decreases human small airway epithelial cells (SAECs) viability with an increase in cleaved caspase-3 activity. 4-HNE augmented the production of mitochondrial ROS, followed by a reduction in mitochondrial oxygen consumption
The dose-dependent response indicates that prolonged hyperoxia exposure and oxidative stress leads to post-translational protein modification, impairing normal cellular processes
Summary
Hyperoxic acute lung injury (HALI) triggers cellular damage and produces reactive oxygen species (ROS) that interfere with the cell’s intrinsic antioxidant responses [1,2,3]. 4-HNE can induce protein dysfunction by forming adducts with lysine, histidine, and cysteine residues, as well as generating stable Michael addition products and disulfide bonds [5, 6]. These detrimental reactions further lead to 4-HNEinduced cellular apoptosis and death [7, 8]. ROS production is well known to enhance lipid peroxidation reactions, damaging proteins within the mitochondrial respiratory chain and reducing oxygen consumption rate [8, 10,11,12]
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