Duke University, Department of Ophthalmology, Durham, NC, 27705, USA.
Duke University, Department of Ophthalmology, Durham, NC, 27705, USA.
Prog Retin Eye Res. 2022 Sep;90:101064. doi: 10.1016/j.preteyeres.2022.101064. Epub 2022 Apr 1.
During the last few years, the autophagy lysosomal system is emerging as a central cellular pathway with roles in survival, acting as a housekeeper and stress response mechanism. Studies by our and other labs suggest that autophagy might play an essential role in maintaining aqueous humor outflow homeostasis, and that malfunction of autophagy in outflow pathway cells might predispose to ocular hypertension and glaucoma pathogenesis. In this review, we will collect the current knowledge and discuss the molecular mechanisms by which autophagy does or might regulate normal outflow pathway tissue function, and its response to different types of stressors (oxidative stress and mechanical stress). We will also discuss novel roles of autophagy and lysosomal enzymes in modulation of TGFβ signaling and ECM remodeling, and the link between dysregulated autophagy and cellular senescence. We will examine what we have learnt, using pre-clinical animal models about how dysregulated autophagy can contribute to disease and apply that to the current status of autophagy in human glaucoma. Finally, we will consider and discuss the challenges and the potential of autophagy as a therapeutic target for the treatment of ocular hypertension and glaucoma.
在过去的几年中，自噬溶酶体系统作为一种具有生存作用的核心细胞途径而出现，充当管家和应激反应机制。我们和其他实验室的研究表明，自噬可能在维持房水流出稳态中发挥重要作用，并且自噬在流出途径细胞中的功能障碍可能导致眼内压升高和青光眼发病机制。在这篇综述中，我们将收集当前的知识，并讨论自噬调节正常流出途径组织功能的分子机制，以及自噬对不同类型应激源（氧化应激和机械应激）的反应。我们还将讨论自噬和溶酶体酶在调节 TGFβ信号和 ECM 重塑中的新作用，以及自噬失调与细胞衰老之间的联系。我们将使用临床前动物模型来研究自噬失调如何导致疾病，并将其应用于人类青光眼的自噬现状，从而检查我们学到的知识。最后，我们将考虑并讨论自噬作为治疗眼内压升高和青光眼的治疗靶点的挑战和潜力。
