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

Abstract

Heatstroke (HS) can cause acute lung injury (ALI). Heat stress induces inflammation and apoptosis via reactive oxygen species (ROS) and endogenous reactive aldehydes. Endothelial dysfunction also plays a crucial role in HS-induced ALI. Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that detoxifies aldehydes such as 4-hydroxy-2-nonenal (4-HNE) protein adducts. A single point mutation in ALDH2 at E487K (ALDH2*2) intrinsically lowers the activity of ALDH2. Alda-1, an ALDH2 activator, attenuates the formation of 4-HNE protein adducts and ROS in several disease models. We hypothesized that ALDH2 can protect against heat stress-induced vascular inflammation and the accumulation of ROS and toxic aldehydes. Homozygous ALDH2*2 knock-in (KI) mice on a C57BL/6J background and C57BL/6J mice were used for the animal experiments. Human umbilical vein endothelial cells (HUVECs) were used for the in vitro experiment. The mice were directly subjected to whole-body heating (WBH, 42°C) for 1 h at 80% relative humidity. Alda-1 (16 mg/kg) was administered intraperitoneally prior to WBH. The severity of ALI was assessed by analyzing the protein levels and cell counts in the bronchoalveolar lavage fluid, the wet/dry ratio and histology. ALDH2*2 KI mice were susceptible to HS-induced ALI in vivo. Silencing ALDH2 induced 4-HNE and ROS accumulation in HUVECs subjected to heat stress. Alda-1 attenuated the heat stress-induced activation of inflammatory pathways, senescence and apoptosis in HUVECs. The lung homogenates of mice pretreated with Alda-1 exhibited significantly elevated ALDH2 activity and decreased ROS accumulation after WBH. Alda-1 significantly decreased the WBH-induced accumulation of 4-HNE and p65 and p38 activation. Here, we demonstrated the crucial roles of ALDH2 in protecting against heat stress-induced ROS production and vascular inflammation and preserving the viability of ECs. The activation of ALDH2 by Alda-1 attenuates WBH-induced ALI in vivo.

Ferroptosis in Rat Lung Tissue during Severe Acute Pancreatitis-Associated Acute Lung Injury: Protection of Qingyi Decoction

“…Many investigations have demonstrated that Alda-1 protects against hyperoxia- or heatstroke-induced ALI. Alda-1 has lung-protective effects by inhibiting ROS generation and endothelial inflammation in the blood vessels [ 31 , 32 ]. Our work showed that mRNA and protein expressions of ALDH2 were considerably decreased in SAP-associated ALI rats' lung tissue.…”

Alda-1 Treatment Alleviates Lung Injury After Cardiac Arrest and Resuscitation in Swine

“…In the setting of sepsis-induced lung injury, Cao et al (17) demonstrated that Alda-1 treatment simultaneously reduced lung pyroptosis and ferroptosis and therefore alleviated its injury in mice. In the setting of heatstroke-induced lung injury, Tsai et al (18) demonstrated that Alda-1 treatment attenuated lung injury through the reduction of reactive oxygen species and toxic aldehydes, and the alleviation of vascular inflammation and endothelial dysfunction in in vitro and in vivo studies. In the case of regional lung IR injury, one study has demonstrated that Alda-1 treatment alleviated oxidative stress, inflammatory response, and apoptosis in human lung vascular endothelial cells and rats' lung tissues (9).…”

Algal Lipids as Modulators of Skin Disease: A Critical Review

“…Other consequences of oxidative stress are oxidative modifications of cellular biomolecules. In such situation, ROS reacts with phospholipid PUFA, leading to lipid peroxidation and ultimately to the formation of reactive aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) [36]. ROS may also indirectly modulate lipid metabolism, since lipid metabolizing enzymes are also over-activated under oxidative stress.…”

“…Nevertheless, ROS can interact not only with transcription factors but also with other proteins, as well as with nucleic acids and especially lipids [46]. ROS react with phospholipids, in particular PUFA, which leads to lipid peroxidation with the generation of reactive aldehydes such as 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) [36].…”