Aldose reductase regulates acrolein-induced cytotoxicity in human small airway epithelial cells

Abstract

Aldose reductase (AR), a glucose metabolizing enzyme, reduces lipid aldehydes and their glutathione conjugates with more than 1000-fold efficiency (Km aldehydes 5-30μM) than glucose. Acrolein, a major endogenous lipid peroxidation product as well as component of environmental pollutant and cigarette smoke, is known to be involved in various pathologies including atherosclerosis, airway inflammation, COPD, and age-related disorders but the mechanism of acrolein-induced cytotoxicity is not clearly understood. We have investigated the role of AR in acrolein-induced cytotoxicity in primary human small airway epithelial cells SAECs. Exposure of SAECs to varying concentrations of acrolein caused cell-death in a concentration- and time-dependent manner. AR inhibition by fidarestat prevented the low (5 to 10 μM) but not high (>10 μM) concentrations of acrolein-induced SAECs cell death. AR inhibition protected SAECs from low dose (5 μM) acrolein-induced cellular reactive oxygen species (ROS). Inhibition of acrolein-induced apoptosis by fidarestat was confirmed by decreased condensation of nuclear chromatin, DNA fragmentation, comet tail-moment, and annexin-V fluorescence. Further, fidarestat inhibited acrolein-induced translocation of pro-apoptotic proteins Bax and Bad from cytosol to the mitochondria, and that of Bcl2 and BclXL from mitochondria to cytosol. Acrolein-induced cytochrome c release from mitochondria was also prevented by AR inhibition. The mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinases 1 and 2 (ERK1/2), stress-activated protein kinases/c-jun NH2-terminal kinases (SAPK/JNK) and p38MAPK, and c-jun were transiently activated in airway epithelial cells by acrolein in a concentration and time-dependent fashion, which were significantly prevented by AR inhibition. These results suggest that AR inhibitors could prevent acrolein-induced cytotoxicity in the lung epithelial cells.

Crosstalk between TGF‐β1 and complement activation augments epithelial injury in pulmonary fibrosis

“…Our previous report demonstrated that IL‐17A‐mediated EMT occurs via TGF‐β1‐dependent signaling, particularly p38MAPK activation (22), and p38MAPK has been implicated in epithelial injury (32). However, the correlation between TGF‐β1‐mediated p38MAPK activation and complement activation‐mediated epithelial injury is unknown.…”

“…p38MAPK has been widely implicated in epithelial injury (22, 32, 41). Accordingly, we observed a role of p38MAPK in protecting against the loss of CIPs.…”

Hesperetin mitigates acrolein-induced apoptosis in lung cellsin vitroandin vivo

“…Similar to other reactive carbonyl species, acrolein is highly reactive with cellular nucleophiles such as proteins, DNA, and RNA. Acrolein readily targets and reacts with sulfhydryl or thiol groups and consequently depletes reduced glutathione (GSH), thioredoxin, and glutaredoxin, which are important antioxidants, therefore, there is increased oxidative stress [8][9][10].…”

Idh2 deficiency exacerbates acrolein-induced lung injury through mitochondrial redox environment deterioration

“…Acrolein readily targets and reacts with the sulfhydryl group of cysteines to form thioether adducts via a Michael addition mechanism [8]. Depletion of cellular reduced glutathione (GSH) by the formation of GS-acrolein conjugates results in increased oxidative stress [9][10][11]. Acrolein can also deplete protein thiols, such as thioredoxin and glutaredoxin, which are important antioxidant proteins [12,13].…”