Aiello Lloyd Paul
Harvard Medical School and Joslin Diabetes Center, Boston, Massachussetts, USA.
Surv Ophthalmol. 2002 Dec;47 Suppl 2:S263-9. doi: 10.1016/s0039-6257(02)00391-0.
Diabetic retinopathy is one of the most debilitating complications of diabetes mellitus. Despite major advances in understanding the pathogenesis of this disease and the efficacy of current therapies, diabetic retinopathy remains the leading cause of new-onset blindness among working-age people. The mainstay of current therapy, laser photocoagulation, is useful in preventing blindness and severe vision loss but is not often effective in restoring lost visual acuity. In addition, troublesome side effects and potentially serious complications may occur. Diabetic retinopathy is characterized by a progression of abnormalities. Nonproliferative retinopathy results from a series of biochemical and cellular changes that ultimately cause progressive retinal ischemia. The subsequent elaboration of growth factors in response to ischemia leads to the development of proliferative retinopathy, which is characterized by aberrant neovacularization of the retina-potentially leading to severe, irreversible visual loss. Increased retinal vascular leakage may also occur at any stage in this process, resulting in macular edema and possible progressive visual impairment. Although numerous biochemical factors are thought to play a role in the development of retinopathy, activation of protein kinase C (PKC), specifically the beta isoform of PKC (PKC beta), is implicated for both the early and late-stage manifestations of retinopathy. Studies suggest that orally administered LY333531, a beta-isoform specific PKC inhibitor, may be effective in ameliorating retinopathy progression, proliferation, and retinal vascular leakage. The status of ongoing clinical trials aimed at addressing the efficacy of PKC beta with regard to diabetes-induced retinal complications and perspectives on the role of PKC beta are presented.
糖尿病性视网膜病变是糖尿病最具致残性的并发症之一。尽管在理解该疾病的发病机制和当前治疗方法的疗效方面取得了重大进展，但糖尿病性视网膜病变仍然是劳动年龄人群新发失明的主要原因。当前治疗的主要方法激光光凝术，有助于预防失明和严重视力丧失，但在恢复已丧失的视力方面往往效果不佳。此外，还可能出现令人烦恼的副作用和潜在的严重并发症。糖尿病性视网膜病变的特征是异常情况不断进展。非增殖性视网膜病变是由一系列生化和细胞变化引起的，最终导致视网膜进行性缺血。随后因缺血而产生的生长因子会导致增殖性视网膜病变的发展，其特征是视网膜异常新生血管形成，这可能导致严重的、不可逆转的视力丧失。在这个过程的任何阶段都可能出现视网膜血管渗漏增加，导致黄斑水肿和可能的进行性视力损害。尽管许多生化因素被认为在视网膜病变的发展中起作用，但蛋白激酶C（PKC）的激活，特别是PKC的β亚型（PKCβ），与视网膜病变的早期和晚期表现都有关联。研究表明，口服LY333531，一种β亚型特异性PKC抑制剂，可能有效改善视网膜病变的进展、增殖和视网膜血管渗漏。本文介绍了旨在探讨PKCβ对糖尿病性视网膜并发症疗效的正在进行的临床试验的情况以及对PKCβ作用的展望。
