CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension.
CXCR3 antagonism of SDF-1(5-67) restores trabecular function and prevents retinal neurodegeneration in a rat model of ocular hypertension.
复制标题
CXCR3 对 SDF-1(5-67) 的拮抗作用可恢复高眼压大鼠模型中的小梁功能并预防视网膜神经变性。
DOI：
10.1371/journal.pone.0037873
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Baudouin C
中科院分区：
文献类型：
--
作者：
Denoyer A;Godefroy D;Célérier I;Frugier J;Degardin J;Harrison JK;Brignole-Baudouin F;Picaud S;Baleux F;Sahel JA;Rostène W;Baudouin C
青光眼是不可逆性失明的最常见原因，是一种神经病变，通常由病理性高眼压引起，原因是小梁网变性的机制尚不清楚。目前的抗青光眼治疗并不针对病因小梁病理，这可能解释了为什么治疗失败，经常观察到。在这里，我们表明，趋化因子CXCL 12，其截短形式SDF-1（5-67），和受体CXCR 4和CXCR 3在人青光眼小梁组织和人小梁细胞系中表达。SDF-1（5-67）在基质金属蛋白酶、TNF-α和TGF-β2的控制下产生，这些因子已知与青光眼有关。CXCL 12通过CXCR 4保护体外小梁细胞免于凋亡性死亡，而SDF-1（5-67）通过CXCR 3和半胱天冬酶活化诱导凋亡。在大鼠中眼部施用SDF-1（5-67）增加眼内压。相比之下，在高眼压大鼠模型中施用选择性CXCR 3拮抗剂降低眼内压，防止视网膜神经变性，并保留视觉功能。CXCR 3拮抗剂的保护作用与小梁功能的恢复有关。这些数据表明，CXCL 12的蛋白水解裂解参与小梁病理生理学，并且局部施用选择性CXCR 3拮抗剂可能是治疗高眼压和随后的视网膜变性的有益治疗策略。
Glaucoma, the most common cause of irreversible blindness, is a neuropathy commonly initiated by pathological ocular hypertension due to unknown mechanisms of trabecular meshwork degeneration. Current antiglaucoma therapy does not target the causal trabecular pathology, which may explain why treatment failure is often observed. Here we show that the chemokine CXCL12, its truncated form SDF-1(5-67), and the receptors CXCR4 and CXCR3 are expressed in human glaucomatous trabecular tissue and a human trabecular cell line. SDF-1(5-67) is produced under the control of matrix metallo-proteinases, TNF-α, and TGF-β2, factors known to be involved in glaucoma. CXCL12 protects in vitro trabecular cells from apoptotic death via CXCR4 whereas SDF-1(5-67) induces apoptosis through CXCR3 and caspase activation. Ocular administration of SDF-1(5-67) in the rat increases intraocular pressure. In contrast, administration of a selective CXCR3 antagonist in a rat model of ocular hypertension decreases intraocular pressure, prevents retinal neurodegeneration, and preserves visual function. The protective effect of CXCR3 antagonism is related to restoration of the trabecular function. These data demonstrate that proteolytic cleavage of CXCL12 is involved in trabecular pathophysiology, and that local administration of a selective CXCR3 antagonist may be a beneficial therapeutic strategy for treating ocular hypertension and subsequent retinal degeneration.
登录
查看更多内容
影响因子：
3.4
作者：
JONES, RF;MAURICE, DM
通讯作者：
MAURICE, DM
影响因子：
3.4
作者：
Danias, J;Shen, F;Mittag, T
通讯作者：
Mittag, T
影响因子：
3.4
作者：
Lu, Zhaozeng;Overby, Darryl R.;Gong, Haiyan
通讯作者：
Gong, Haiyan
影响因子：
12.4
作者：
Khan, M. Z.;Brandimarti, R.;Meucci, O.
通讯作者：
Meucci, O.
影响因子：
4.1
作者：
Bhutto, I. A.;McLeod, D. S.;Lutty, G. A.
通讯作者：
Lutty, G. A.