| Objective To observe changes of the ultrastructure and activity of hypothalamic-pituitary-adrenal (HPA) axis in rats exposed to intermittent hypoxia (IH), to explore the possible mechanism of the dysregulation of HPA axis by IH rat model imitating the pathophysiological processes of hypoxia/normoxia in OSAHS patients, and further to investigate the interventional role of reduced glutathione (GSH) to provide a new direction for the clinical prevention and treatment of OSAHS and its comorbidities.Methods Firstly,24 male Sprague-Dawley rats were randomly divided into three groups of 8 in each group:normoxia control (NC) group, intermittent hypoxia (IH) group and GSH therapeutic intermittent hypoxia (IH+GSH) group. The rats of IH and IH+GSH group were respectively placed into the same chambers in which the level of oxygen was monitored and regulated by time-controlled valves connected to N2, O2 and compressed air. Briefly, each episodic hypoxia cycle lasted for 120 seconds, including hypoxia period with N2 for 30s and resting for 10s, and reoxygenation period with O2 for 20s and compressed air for 60s to oxygen concentration in the capsule dropping to 6%-7% and gradually rising to 20%-21%. Rats in NC group were exposed to the same timer- and valve-controlled changes as IH at normoxia levels throughout the protocol. Rats were exposed to 8 hours per day (9 a.m-5p.m) during the light portion of the cycle for 4 weeks. Secondly, based on intermittent hypoxic ventilation, each rat of IH+GSH group was given GSH 500 mgkg-1·d-1 by regularly intraperitoneal injection, while rats of NC group and IH group were simultaneously injected equal volume of normal saline. After 4 weeks, we collected arterial blood of all rats via abdominal aortic puncture. Serum levels of MDA, SOD and GSH-Px were detected by chemical colorimetric method, and radioimmunoassay was used to examine levels of TNF-a, IL-6, ACTH and CORT. Furthermore, the ultra-structure of pituitary and adrenal cortex in rats was observed by transmission electron microscope (TEM).Results In the first part, compared with NC group, the contents of MDA, TNF-a, IL-6, ACTH and CORT in IH group were significantly higher, while the activities of SOD and GSH-Px were remarkably lower (all P<0.05). Moreover, the contents of ACTH and CORT were associated respectively with the levels of MDA, TNF-a and IL-6 positively, but negatively correlated with the activities of SOD and GSH-Px. There was a significant correlation between ACTH and CORT. Furthermore, we have dynamically observed the influence of IH on the ultrastructure of HPA axis by TEM. In the second part, IH+GSH group with the interventional role of GSH showed a significant decrease in the levels of MDA, TNF-a, IL-6, ACTH and CORT, and increase in the activities of SOD and GSH-Px (all P<0.05). Compared with IH group, the ultrastructural damages of hypothalamus, pituitary and adrenal cortex were reversed by GSH to a certain extent in IH+GSH group.Conclusions IH can cause oxidative stress and inflammatory reaction, which may be a stressor to stimulate the HPA axis, resulting in its disrupted ultrastructure and function. GSH may have certain interventional effect for the HPA axis through the promotion of free radical scavenging and enhancement of antioxidation to relieve oxidative damage and reduce inflammation induced by IH. |
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