Genomic and proteomic pathophysiology of pseudoexfoliation glaucoma.
Genomic and proteomic pathophysiology of pseudoexfoliation glaucoma.
复制标题
DOI：
10.1097/iio.0000000000000047
复制
发表时间：
2014
影响因子：
--
通讯作者：
Lee RK
中科院分区：
文献类型：
--
作者：
Vazquez LE;Lee RK
PEX起源于涉及交联基因赖氨酰氧化酶样-1（LOXL 1）的病理性弹性变性过程，并且与弹性细胞外基质的异常形成相关。我们先前描述了一种蛋白质汇模型，以解释PEX材料沉积在透镜囊膜和其他眼内表面上。最近的研究结果不仅提供了支持这一假设的证据，而且进一步加深了我们对疾病基本过程的理解。致病过程的一个关键方面是PEXG中血-房水屏障完整性的损害。L0 XL 1水平的降低与弹性蛋白掺入弹性组织（包括血管的弹性膜）的降低相关。这导致未掺入的弹性蛋白作为可溶性弹性蛋白释放，以及血清蛋白、炎性细胞因子和细胞外基质组分渗漏到房水中。这最终导致大蛋白复合物或PEX材料在整个眼内表面的聚集和沉淀，如蛋白库模型中所述。病理性PEX过程也影响弹性组织的生物力学性质，例如小梁网、透镜小带和筛板。这可能是细胞外基质蛋白质内在改变的主要病理过程的一部分。这些组织的结构组成的这种根本性变化可能会改变它们的刚度、弹性和其他生物力学特性。这可能有助于增加小梁网流出阻力和高眼内压，以及对筛板处视网膜神经节细胞轴突的机械损伤，这有助于青光眼。这些病理生理过程相结合可能是PEXG中观察到的一些临床特征的基础。
PEX stems from a pathologic elastotic process involving the cross-linking gene lysyl oxidase-like-1 (LOXL1), and is associated with abnormal formation of elastic extracellular matrix. We previously described a protein sink model to explain PEX material deposition on the lens capsule and other intraocular surfaces. Recent research findings not only provide evidence to support this hypothesis, but also further our understanding of the fundamental disease process. A key aspect of the pathogenic process is the compromise of blood-aqueous barrier integrity in PEXG. Decreased level of LOXL1 is associated with decreased elastin incorporation into elastic tissues, including the elastic lamina of blood vessels. This results in unincorporated elastin that is released as soluble elastin, and leakage of serum proteins, inflammatory cytokines, and extracellular matrix components into aqueous humor. This ultimately leads to aggregation and precipitation of large protein complexes, or PEX material, throughout intraocular surfaces as described in the protein sink model. The pathologic PEX process also affects the biomechanical properties of elastic tissues, such as the trabecular meshwork, lens zonules, and lamina cribrosa. This may be part of the primary pathologic process with intrinsically altered extracellular matrix proteins. This fundamental change in the structural composition of these tissues may alter their rigidity, elasticity, and other biomechanical properties. This likely contributes to increased trabecular meshwork outflow resistance and high intraocular pressure, and mechanical injury to retinal ganglion cell axons at the lamina cribrosa, which are conducive to glaucoma. These pathophysiologic processes combined may underlie some of the clinical hallmarks observed in PEXG.