关键词: 慢性间歇性低氧, 铁死亡, 内质网应激, 肺损伤

Abstract: Objective　To evaluate the effects of chronic intermittent hypoxia (CIH) on lung tissue structure and function by establishing a rat model of CIH to simulate the pathological pattern of obstructive sleep apnea (OSA). To investigate the roles of ferroptosis and endoplasmic reticulum stress (ERS) in CIH-induced lung injury, so as to provide new ideas for the clinical prevention and treatment of OSA related lung diseases.Methods　Eighteen male SD rats were randomly divided into 3 groups with 6 rats in each group, control (CON) group, CIH group, and CIH+Fer-1 (FIH) group. They were exposed to normoxic or CIH environment respectively. From the 5th week, the FIH group was intraperitoneally injected with Fer-1 [2 mg/(kg·d)], and the CON group and CIH group were injected with equal volume of 2% dimethyl sulfoxide (DMSO). At the end of the 8th week, the rats were sacrificed, and HE and Masson staining were used to observe the pathological changes of lung tissue, and TUNEL staining was used to analyze cell apoptosis. According to the kit instructions, the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA), glutathione (GSH), 4-hydroxynonenal (4-HNE), reactive oxygen species (ROS), glutathione peroxidase 4 (GPX4), and Fe2+ were measured. Western blot was used to detect the expression of key proteins in the ERS pathway.Results　Compared with the CON group, the CIH group showed thickening of the alveolar wall, increased infiltration of inflammatory cells in the alveoli, and mild alveolar dilatation in rats. Partial collagen fiber hyperplasia was observed in the pulmonary interstitium, and the number of apoptotic cells was significantly increased, The levels of inflammatory factors (IL-6, IL-1β, and TNF-α) were elevated, Oxidative stress was aggravated (GSH content decreased, 4-HNE content increased), Ferroptosis markers were abnormal (ROS and Fe2+ levels were significantly increased, GPX4 content was decreased), The relative content of eIF2α protein in the ERS pathway was increased(P<0.05). Compared with CIH group, the lung tissue injury and pulmonary fibrosis were alleviated in rats of FIH group, with a significant reduction in the apoptosis rate, Meanwhile, the levels of IL-6 and TNF-α were decreased, and a notable decrease in the levels of 4-HNE, Fe2+, and ROS, whereas the content of GPX4 was increased (P<0.05).Conclusion　Ferroptosis and ERS are involved in CIH-induced lung injury, and Fer-1 effectively alleviates lung injury by inhibiting inflammation, oxidative stress, ERS, and apoptosis.

Key words: chronic intermittent hypoxia, ferroptosis, endoplasmic reticulum stress, lung injury