Hypoxia adaptation in the cornea: Current animal models and underlying mechanisms

The cornea is an avascular, transparent tissue that is essential for visual function. Any disturbance to the corneal transparency will result in a severe vision loss. Due to the avascular nature, the cornea acquires most of the oxygen supply directly or indirectly from the atmosphere. Corneal tissue hypoxia has been noticed to influence the structure and function of the cornea for decades. The etiology of hypoxia of the cornea is distinct from the rest of the body, mainly due to the separation of cornea from the atmosphere, such as prolonged contact lens wearing or closed eyes. Corneal hypoxia can also be found in corneal inflammation and injury when a higher oxygen requirement exceeds the oxygen supply. Systemic hypoxic state during lung diseases or high altitude also leads to corneal hypoxia when a second oxygen consumption route from aqueous humor gets blocked. Hypoxia affects the cornea in multiple aspects, including disturbance of the epithelium barrier function, corneal edema due to endothelial dysfunction and metabolism changes in the stroma, and thinning of corneal stroma. Cornea has also evolved mechanisms to adapt to the hypoxic state initiated by the activation of hypoxia inducible factor (HIF). The aim of this review is to introduce the pathology of cornea under hypoxia and the mechanism of hypoxia adaptation, to discuss the current animal models used in this field, and future research directions.