目的:经典补体途径的激活被认为有助于青光眼的发展和进展。替代补体或扩增途径在青光眼中的作用尚不清楚。我们评估了在光聚合透明质酸甲基丙烯酸缩水甘油酯(HAGM)诱导的青光眼小鼠高眼压模型中,有或没有青光眼的死后人类眼组织中补体因子B(FB)的表达以及FB抑制和缺失的影响。方法:通过RNAscope和TaqMan评估人眼中的人CFBmRNA。在C57BL6/J小鼠上进行HAGM模型。用口服FB抑制剂和Cfb-/-小鼠评价FB在HAGM模型中的作用。通过TaqMan和蛋白质印迹评估小鼠眼睛中的补体mRNA和蛋白质,分别。结果:人青光眼黄斑神经视网膜和视神经头的CFBmRNA表达上调。CfbmRNA在HAGM模型中也上调。口服FB抑制剂,在野生型小鼠中,在眼内压(IOP)诱导后,每天以200mg/kg给药持续3天的ED-79-GX17在眼部组织中显示出补体抑制,并且显著抑制全身补体水平。每天给药30天的ED-79-GX17或Cfb缺失也不能防止小鼠中IOP诱导后30天的视网膜神经节细胞或轴突损失。结论:尽管Cfb表达上调和替代途径激活,但替代补体成分FB可能不会在HAGM小鼠青光眼模型中引起RGC丢失。这些发现与人类青光眼的相关性尚待确定。
Purpose: Activation of the classical complement pathway is thought to contribute to the development and progression of glaucoma. The role of alternative complement or amplification pathways in glaucoma is not well understood. We evaluated complement factor B (
FB) expression in postmortem human ocular tissues with or without glaucoma and the effect of
FB inhibition and deletion in a mouse ocular hypertensive model of glaucoma induced by photopolymerized hyaluronic acid glycidyl methacrylate (HAGM). Methods: Human CFB mRNA in human eyes was assessed by RNAscope and TaqMan. HAGM model was performed on C57BL6/J mice. The effect of
FB in HAGM model was evaluated with an oral
FB inhibitor and Cfb-/- mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. Results: CFB mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. Cfb mRNA is also upregulated in the HAGM model. Oral
FB inhibitor, ED-79-GX17, dosed daily at 200 mg/kg for 3 days after intraocular pressure (IOP) induction in wild-type mice showed complement inhibition in ocular tissues and significantly inhibited systemic complement levels. Daily dosing of ED-79-GX17 for 30 days or Cfb deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. Conclusion: The alternative complement component
FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of Cfb expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.