New pathogenetic insights into pseudoexfoliation syndrome/glaucoma. Therapeutically relevant?
New pathogenetic insights into pseudoexfoliation syndrome/glaucoma. Therapeutically relevant?
复制标题
DOI：
10.1007/s00347-012-2531-1
复制
发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Schloetzer-Schrehardt, U.
中科院分区：
文献类型：
--
作者：
Schloetzer-Schrehardt, U.
假性剥脱（PEX）综合征是一种由基因决定的、普遍的细胞外基质疾病，导致异常纤维材料在各种眼内和眼外组织（包括小梁网）中进行性沉积。因此，它是开角型青光眼最常见的可识别原因，也是全世界失明的主要原因。 PEX 特异性纤维化基质过程是一种应力诱导的弹性变性，其特征是弹性微原纤维过度生成和异常交联成纤维状 PEX 聚集体。触发这种纤维化过程的共同调节因素包括纤维生长因子浓度升高（例如 TGF-β1）、蛋白水解酶活性降低、微妙的炎症过程和各种外部应激因素（例如氧化应激）。遗传学研究发现 LOXL1（赖氨酰氧化酶样 1）基因的多个多态性与 PEX 综合征和 PEX 青光眼之间存在高度显着的关联。由于发现这些 LOXL1 风险变异发生在全球所有地理人群中几乎 100% 的 PEX 患者中，因此 LOXL1 似乎代表了 PEX 表型表现的主要风险因素。 LOXL1 是细胞外基质代谢中的关键交联酶，似乎是弹性纤维形成和稳定所特别需要的。现有数据表明，LOXL1 酶功能和表达在 PEX 组织中失调，从而在青光眼发展中发挥核心作用。一方面，LOXL1和弹性纤维成分表达的增加有助于在流出通路中形成异常交联的PEX聚集体，导致流出阻力和眼内压增加。另一方面，LOXL1 表达减少和组织水平不足可能导致退行性组织改变，特别是在筛板中，从而对该关键组织的生物力学特性产生不利影响。这种 PEX 特异性筛板弹性蛋白病变使得 PEX 眼睛更容易受到压力引起的视神经损伤，可能构成青光眼发展的独立危险因素。这些发现可能对 PEX 患者的临床管理产生直接影响，强调需要准确的诊断、严格的降眼压治疗以及密切和定期的随访。
Pseudoexfoliation (PEX) syndrome is a genetically determined, generalized disease of the extracellular matrix leading to the progressive deposition of an abnormal fibrillar material in various intraocular and extraocular tissues including the trabecular meshwork. It thus represents the most common identifiable cause of open-angle glaucoma and a leading cause of blindness worldwide. The PEX-specific fibrotic matrix process, a stress-induced elastosis, is characterized by an excessive production and abnormal cross-linking of elastic microfibrils into fibrillar PEX aggregates. Co-modulating factors triggering this fibrotic process include elevated concentrations of fibrogenic growth factors, such as TGF-beta 1, reduced activity of proteolytic enzymes, subtle inflammatory processes and various external stress factors, such as oxidative stress. Genetic studies identified a highly significant association between several polymorphisms in the LOXL1 (lysyl oxidase-like 1) gene with both PEX syndrome and PEX glaucoma. As these LOXL1 risk variants were found to occur in almost 100% of PEX patients throughout all geographical populations worldwide, LOXL1 appears to represent a principal risk factor for manifestation of the PEX phenotype. LOXL1 is a pivotal cross-linking enzyme in extracellular matrix metabolism and seems to be specifically required for elastic fiber formation and stabilization. The available data suggest that LOXL1 enzyme function and expression are dysregulated in PEX tissues and thereby play a central role in glaucoma development. On the one hand, increased expression of LOXL1 and elastic fiber components contributes to the formation of abnormally cross-linked PEX aggregates in the outflow pathways leading to increased outflow resistance and intraocular pressure. On the other hand, reduced expression and inadequate tissue levels of LOXL1 may lead to degenerative tissue alterations, particularly in the lamina cribrosa adversely affecting the biomechanical properties of this critical tissue. This PEX-specific elastinopathy of the lamina cribrosa rendering PEX eyes more vulnerable to pressure-induced optic nerve damage may constitute an independent risk factor for glaucoma development. The findings may have direct consequences for the clinical management of PEX patients underlining the need for an exact diagnosis, a strict IOP-reducing therapy and a close and regular follow-up.