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PNAS:急性青光眼或是一种炎症性疾病
    更新时间:2015-12-24 查看次数:1976

2014年7月16日讯 /生物谷BIOON/--近日,中美研究人员合作发现,小鼠急性青光眼在很大程度上是一种炎症性疾病,眼部压力升高或是通过炎症反应来导致视力丧失的。

这项研究发表在PNAS杂志上,这对所谓的急性闭角型青光眼的治疗具有非常重要的临床意义。研究是首次揭示了高眼压导致急性青光眼患者视力减退的炎症机制。

青光眼是指眼内压间断或持续升高的一种常见疑难眼病。青光眼是导致人类失明的三大致盲眼病之一,根据前房前角的形态及发病缓急,又分为急,慢性闭角型青光眼。急性闭角型青光眼往往是一个令人痛苦的眼科急诊,患者有一个突然上升的眼压和视力的直接损伤。

在这项研究中,研究人员发现,小鼠眼内压快速,持续大幅度的增高会开启基因(TLR4),导致caspase-8蛋白的激活。反过来这个信号蛋白触发那些通常有助于哺乳动物对抗微生物感染的炎性蛋白质的生成。

免疫反应是一把双刃剑,因为在正常情况下,对抗微生物感染的炎性蛋白保护我们免受感染,但在急性青光眼的情况下,炎性反应会刺激视网膜细胞的细胞凋亡(程序性细胞死亡)。

为了进一步证实高眼压与视网膜损伤的炎性机制联系,研究人员发现:可以通过抑制TLR4基因或caspace-8蛋白,减缓急性青光眼小鼠的视网膜细胞死亡。(生物谷Bioon.com)

Caspase-8 promotes NLRP1/NLRP3 inflammasome activation and IL-1β production in acute glaucoma

Wei Chi, et al.

Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1β expression and RGC death via a caspase-1–dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1–independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1β production and RGC death and highlight signal transduction in a caspase-1–dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1–independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.