Department of Ophthalmology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003, China.
Department of Endocrinology, Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, 310052, China.
Cell Death Dis. 2022 May 31;13(5):513. doi: 10.1038/s41419-022-04963-x.
Phosphatidylinositol 3 kinase (PI3K)/AKT (also called protein kinase B, PKB) signalling regulates various cellular processes, such as apoptosis, cell proliferation, the cell cycle, protein synthesis, glucose metabolism, and telomere activity. Corneal epithelial cells (CECs) are the outermost cells of the cornea; they maintain good optical performance and act as a physical and immune barrier. Various growth factors, including epidermal growth factor receptor (EGFR) ligands, insulin-like growth factor 1 (IGF1), neurokinin 1 (NK-1), and insulin activate the PI3K/AKT signalling pathway by binding their receptors and promote antiapoptotic, anti-inflammatory, proliferative, and migratory functions and wound healing in the corneal epithelium (CE). Reactive oxygen species (ROS) regulate apoptosis and inflammation in CECs in a concentration-dependent manner. Extreme environments induce excess ROS accumulation, inhibit PI3K/AKT, and cause apoptosis and inflammation in CECs. However, at low or moderate levels, ROS activate PI3K/AKT signalling, inhibiting apoptosis and stimulating proliferation of healthy CECs. Diabetes-associated hyperglycaemia directly inhibit PI3K/AKT signalling by increasing ROS and endoplasmic reticulum (ER) stress levels or suppressing the expression of growth factors receptors and cause diabetic keratopathy (DK) in CECs. Similarly, hyperosmolarity and ROS accumulation suppress PI3K/AKT signalling in dry eye disease (DED). However, significant overactivation of the PI3K/AKT signalling pathway, which mediates inflammation in CECs, is observed in both infectious and noninfectious keratitis. Overall, upon activation by growth factors and NK-1, PI3K/AKT signalling promotes the proliferation, migration, and anti-apoptosis of CECs, and these processes can be regulated by ROS in a concentration-dependent manner. Moreover, PI3K/AKT signalling pathway is inhibited in CECs from individuals with DK and DED, but is overactivated by keratitis.
磷脂酰肌醇 3 激酶（PI3K）/AKT（也称为蛋白激酶 B，PKB）信号通路调节多种细胞过程，如细胞凋亡、细胞增殖、细胞周期、蛋白质合成、葡萄糖代谢和端粒活性。角膜上皮细胞（CECs）是角膜的最外层细胞；它们维持良好的光学性能，并充当物理和免疫屏障。各种生长因子，包括表皮生长因子受体（EGFR）配体、胰岛素样生长因子 1（IGF1）、神经激肽 1（NK-1）和胰岛素，通过与其受体结合激活 PI3K/AKT 信号通路，促进角膜上皮细胞（CE）的抗凋亡、抗炎、增殖和迁移功能及伤口愈合。活性氧（ROS）以浓度依赖的方式调节 CECs 的细胞凋亡和炎症。极端环境会导致 ROS 过度积累，抑制 PI3K/AKT，引起 CECs 的细胞凋亡和炎症。然而，在低或中等水平下，ROS 会激活 PI3K/AKT 信号通路，抑制健康 CECs 的凋亡并刺激其增殖。糖尿病相关的高血糖通过增加 ROS 和内质网（ER）应激水平或抑制生长因子受体的表达直接抑制 PI3K/AKT 信号通路，导致 CECs 的糖尿病性角膜病变（DK）。同样，高渗和 ROS 积累会抑制干眼症（DED）中 PI3K/AKT 信号通路。然而，PI3K/AKT 信号通路在感染性和非感染性角膜炎中均显著过度激活，介导 CECs 的炎症。总的来说，PI3K/AKT 信号通路在受到生长因子和 NK-1 激活后，促进 CECs 的增殖、迁移和抗凋亡，而这些过程可以通过 ROS 以浓度依赖的方式进行调节。此外，DK 和 DED 患者的 CECs 中 PI3K/AKT 信号通路被抑制，但由角膜炎过度激活。
