Abstract
Central nervous system and visual dysfunction is an unfortunate consequence of systemic hypoxia in the setting of cardiopulmonary disease, including infection with SARS-CoV-2, high-altitude cerebral edema and retinopathy and other conditions. Hypoxia-induced inflammatory signaling may lead to retinal inflammation, gliosis and visual disturbances. We investigated the consequences of systemic hypoxia using serial retinal optical coherence tomography and by assessing the earliest changes within 24h after hypoxia by measuring a proteomics panel of 39 cytokines, chemokines and growth factors in the plasma and retina, as well as using retinal histology. We induced severe systemic hypoxia in adult C57BL/6 mice using a hypoxia chamber (10% O2) for 1 week and rapidly assessed measurements within 1h compared with 18h after hypoxia. Optical coherence tomography revealed retinal tissue edema at 18h after hypoxia. Hierarchical clustering of plasma and retinal immune molecules revealed obvious segregation of the 1h posthypoxia group away from that of controls. One hour after hypoxia, there were 10 significantly increased molecules in plasma and 4 in retina. Interleukin-1β and vascular endothelial growth factor were increased in both tissues. Concomitantly, there was significantly increased aquaporin-4, decreased Kir4.1, and increased gliosis in retinal histology. In summary, the immediate posthypoxic period is characterized by molecular changes consistent with systemic and retinal inflammation and retinal glial changes important in water transport, leading to tissue edema. This posthypoxic inflammation rapidly improves within 24h, consistent with the typically mild and transient visual disturbance in hypoxia, such as in high-altitude retinopathy. Given hypoxia increases risk of vision loss, more studies in at-risk patients, such as plasma immune profiling and in vivo retinal imaging, are needed in order to identify novel diagnostic or prognostic biomarkers of visual impairment in systemic hypoxia.
Highlights
Systemic hypoxia is a common cause of central nervous system (CNS) dysfunction in many diseases, such as pulmonary hypertension, congestive heart failure [1], cardiac arrest [2, 3], high altitude disease [4, 5], obstructive sleep apnea [6, 7], drowning [8, 9], and most recently SARS-CoV-2 infection [10]
1h after hypoxia, there was a significant 5 μm decrease in total retina thickness (TRT) on optical coherence tomography (OCT) compared to baseline
Severe systemic hypoxia leads to systemic and retina inflammation characterized by increased levels of several proteins including vascular endothelial growth factor (VEGF) and IL-1β in both tissues and retinal structural changes, glial reactivity and imbalanced osmotic and water regulation
Summary
Systemic hypoxia is a common cause of central nervous system (CNS) dysfunction in many diseases, such as pulmonary hypertension, congestive heart failure [1], cardiac arrest [2, 3], high altitude disease [4, 5], obstructive sleep apnea [6, 7], drowning [8, 9], and most recently SARS-CoV-2 infection [10]. In humans exposed to high-altitude hypoxia, it is common to experience visual disturbances, such as changes in color vision [13,14,15], high altitude retinopathy [16, 17], optic disc edema [18, 19] and alterations in multiple electroretinography (ERG) parameters [20]. Fundus photography of high altitude retinopathy and optic neuropathy revealed prominent retinal vascular changes including retinal hemorrhages [17, 22], vascular engorgement and tortuosity and disc hyperemia [23, 24], consistent with a combination of hypoxia-induced ischemia and inflammation [25]. CNS effects of systemic hypoxia outside the eye include headache and other symptoms of acute mountain sickness (nausea, dizziness, fatigue) and high altitude cerebral edema, which is a life-threatening stage [5, 26], memory disturbance and depression [7]
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