In recent years, some studies have reported a correlation between RNFL thickness and high-altitude retinopathy.
16 For example, Tian et al.
17 found that the thickness of RNFL and GCL increased significantly after rapid exposure to a high-altitude environment in Tibet. Yin et al.
18 quantitatively analyzed changes in the retinal structure of 109 healthy subjects during acute exposure to high altitude (3700 m) using spectral domain optical coherence tomography (OCT) and found that high-altitude environments increased the RNFL thickness and macular thickness. Ma et al.
19 also found that compared with healthy high-altitude residents, high-altitude residents with high-altitude polycythemia had a significant increase in RNFL thickness. The current study also confirmed that mouse retinal nerve fiber (RNF) and GCL exhibited varying degrees of thickening after acute HAE, consistent with the aforementioned studies. So far, although the exact pathological and physiological mechanisms underlying acute exposure to high-altitude areas leading to retinal RNFL and GCL thickening remain elusive, numerous studies have shown that altitude-related hypoxia may be the main factor causing changes in RNFL and GCL thickness. First, the retina is one of the most metabolically active tissues in the human body. It has two blood circulation systems, namely the choroidal circulation system, which supplies the outer layer of the retina, and the retinal circulation system, which supplies the inner layer of the retina. The retinal blood flow is strictly regulated by tissue oxygen tension (PO
2). A decrease in the arterial partial pressure of oxygen (PaO
2) immediately causes an increase in retinal blood flow.
20,21 The superficial capillary network of retinal blood vessels is mainly distributed in the GCL of the retina. In addition, the capillary plexus around the radial papilla is located in the RNFL. Therefore, altitude-related hypoxia-induced vasodilation can particularly lead to RNFL and GCL thickening. A study on long-term low-pressure hypoxia in mountaineers at the highest altitude of 5300 meters reported a significant increase in retinal blood flow. They found that the retinal blood flow increased by 89% within 2 hours of reaching the altitude, increased by 128% after 5 days compared with the control blood flow, and increased by 174% after 7 weeks.
21 Yang et al. also confirmed that short-term exposure to high altitude can cause a significant increase in the retinal vein diameter.
22 Second, hypobaric hypoxia has been found to directly damage the tight junctions of retinal endothelial cells by stimulating the production and release of inflammatory factors,
23,24 mediating oxidative stress,
25 damaging the inner blood-retinal barrier, and causing vascular retinal edema. In addition, previous studies have shown that RGCs are particularly sensitive to acute and transient hypoxic stress. Hypoxia-induced activation of nitric oxide synthase (NOS), excessive release of glutamate, and increased intracellular calcium ion can lead to mitochondrial dysfunction in RGCs, resulting in toxic edema and death of RGCs, which are the main factors associated with RGC loss.
26,27 Meanwhile, RGC swelling is also considered a component of retinal edema. We also confirmed through TEM analysis of the ultrastructure of RGCs that cell bodies, axons, and organelles (such as mitochondria) of RGCs undergo edema after acute HAE. Additionally, retinal H&E staining showed that the RNF and GCL thicknesses increased with exposure time in mice exposed to 5000 m altitude conditions and were highest at 10 hours of hypoxia exposure, decreased at 24 hours, and then increased again at 72 hours. We believe that the above trend of changes is the result of a series of adaptive adjustments made by the body to cope with the challenge of low-pressure hypoxia. Although there is currently a general understanding of systemic changes associated with adaptation to HAE, the potential molecular and cellular processes have not been fully elucidated and warrant further research.