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Role of Ferroptosis and Endoplasmic Reticulum Stress in Chronic Intermittent
Hypoxia-Induced Lung Injury
- NIE Tingyu, ZHAO Libo, XUE Xin, RUI Dong, LI Tianjiao, ZHANG Mingru, HAN Jiming, LIU Lin
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2025, 42(6):
34-40.
DOI: 10.3969/ j. issn.1006-6179.2025.06.006
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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.
