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The involvement of oxidative stress and the TLR4/NF-κB/NLRP3 pathway in acute lung injury induced by high-altitude hypoxia

氧化应激 缺氧(环境) TLR4型 NF-κB 高海拔对人类的影响 医学 细胞生物学 化学 生物 氧气 内科学 信号转导 解剖 有机化学
作者
Wangjie Cao,Yuanding Zeng,Yun Su,Hongxia Gong,Jianzheng He,Yongqi Liu,Congyi Li
出处
期刊:Immunobiology [Elsevier BV]
卷期号:229 (3): 152809-152809
标识
DOI:10.1016/j.imbio.2024.152809
摘要

This study investigated the effect of oxidative stress and the TLR4/NF-κB/NLRP3 pathway on the pathogenesis of acute lung injury (ALI) induced by high-altitude hypoxia. Rats were placed in an animal hyperbaric oxygen chamber to establish a rat model of ALI induced by high-altitude hypoxia after treatment with N-acetylcysteine (NAC; a reactive oxygen species [ROS] inhibitor) or/and MCC950 (an NLPR3 inflammasome inhibitor). After modeling, the wet-to-dry weight ratio (W/D) of rat lung tissues was calculated. In lung tissues, ROS levels were detected with immunofluorescence, the enzyme activity was tested with the kit, and the expression of TLR4/NF-κB/NLRP3 pathway-related genes and proteins was measured with western blotting and qRT-PCR. The levels of inflammatory factors in the serum were quantified with ELISA. After modeling, rats showed significantly increased W/D, ROS levels, and Malondialdehyde (MDA) concentrations and markedly diminished Superoxide dismutase (SOD) and Glutathione (GSH) concentrations in lung tissues (all P < 0.01), accompanied by substantially enhanced serum levels of TNF-α, IL-6, and IL-1β, significantly reduced serum levels of IL-10, and remarkably augmented TLR4, NLRP3, p-NF-κB p65, NF-κB p65 mRNA, and Caspase-1 expression in lung tissues (all P < 0.01). Furthermore, treatment with NAC or MCC950 alone or in combination prominently lowered the W/D of lung tissues (P < 0.01), serum levels of TNF-α (P < 0.05), IL-6 (P < 0.05), and IL-1β (P < 0.01), and NF-κB p65 expression and phosphorylation (P < 0.05, P < 0.01) while significantly increasing SOD and GSH concentrations (P < 0.05, P < 0.01) and serum levels of IL-10 (P < 0.01) in modeled rats. Meanwhile, treatment of NAC alone or combined with MCC950 significantly reduced MDA concentration and ROS levels (P < 0.05, P < 0.01) in modeled rats, and treatment of MCC950 alone or combined with NAC considerably declined TLR4, NLRP3, and Caspase-1 expression in modeled rats (P < 0.05, P < 0.01). Inhibition of oxidative stress and the TLR4/NF-κB/NLRP3 pathway can ameliorate ALI in rats exposed to high-altitude hypoxia.
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