Role of the Receptor for Advanced Glycation End Products in Heat Stress-Induced Endothelial Hyperpermeability in Acute Lung Injury

Abstract

Objective: To study the role of the receptor for advanced glycation end products (RAGE) in endothelial barrier dysfunction induced by heat stress, to further explore the signal pathway by which RAGE contributes to heat-induced endothelia response, and thereby find a novel target for the clinical treatment of ALI (acute lung injury) induced by heatstroke. Methods: This study established the animal model of heatstroke using RAGE knockout mice. We observed the role of RAGE in acute lung injury induced by heatstroke in mice by evaluating the leukocytes, neutrophils, and protein concentration in BALF (Bronchoalveolar lavage fluids), lung wet/dry ratio, histopathological changes, and the morphological ultrastructure of lung tissue and arterial blood gas analysis. To further study the mechanism, we established a heat stress model of HUVEC and concentrated on the role of RAGE and its signal pathway in the endothelial barrier dysfunction induced by heat stress, measuring Transendothelial electrical resistance (TEER) and western blot. Results: RAGE played a key role in acute lung injury induced by heatstroke in mice. The mechanism C-Jun is located in the promoter region of the RAGE gene. C-Jun increased the RAGE protein expression while HSF1 suppressed RAGE protein expression. The overexpressed RAGE protein then increased HUVEC monolayer permeability by activating ERK and P38 MAPK under heat stress. Conclusion: This study indicates the critical role of RAGE in heat stress-induced endothelial hyperpermeability in acute lung injury and suggests that RAGE could be a potential therapeutic target in protecting patients against acute lung injury induced by heatstroke.

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

“…Increased immune cells in BALF could be due to endothelial activation/dysfunction and recruitment of inflammatory cells. Consistent with previous studies ( 14 , 17 ), We have found that there were increased total cells in the BALF in mice subjected to HS. A recent study regarding hyperoxia induced ALI also revealed that pretreatment with Alda-1 reduced hyperoxia induced immune cell infiltration, alveolar damage and lung inflammation and preserved alveolar permeability through the activation of Akt and mTOR pathways ( 35 ).…”

“…Through HS clearly induces endothelial barrier dysfunction and hyperpermeability (13)(14)(15)(16)(17), the potential role of hydrostatic lung edema formation in HS induced ALI models are otherwise limited. Accumulated ROS also induced lung edema formation through downregulation of alveolar epithelial Na/K-ATPase activity with impaired alveolar fluid reabsorption (81).…”

“…HS significantly elevates the levels of cytokines in BALF and activates the NF-κB signaling pathway in lung tissue ( 61 ). HS induces p38 activation and inflammatory signaling, apoptosis and pyroptosis in vascular cells ( 14 , 15 , 17 , 62 ). Consistent with previous studies, we also found that mice subjected to HS had increased accumulation of ROS and 4-HNE ( 18 ).…”

“…Endothelial cells (ECs) play an essential role in maintaining the stability of microvascular permeability. Heat stress induces cellular senescence, apoptosis and pyroptosis in a variety of cell types, and endothelial activation/dysfunction with hyperpermeability play crucial roles in HS-induced ALI (13)(14)(15)(16)(17). The accumulation of toxic aldehydes and oxidative stress and upregulation of the NF-kB signaling pathway have been found in the hippocampus and lung tissues of rats subjected to HS (18,19).…”

Anti-Inflammatory and Anti-Oxidative Effects of Isorhamnetin for Protection Against Lung Injury in a Rat Model of Heatstroke in a Dry-Heat Environment

“…Excessive heat exposure and subsequent exposure to harmful substances, such as pro-inflammatory mediators, can increase pulmonary microvascular and epithelial permeability [ 5 ], resulting in the accumulation of large amounts of fluid and proteins in the interstitium and alveolar spaces. The process of abnormal pulmonary edema fluid accumulation impairs alveolar gas exchange, which is an important cause of ALI and respiratory failure related to heatstroke [ 6 , 7 ].…”