Liu Yang, Zhu Min, Gong Ruowen, Wang Xin, Li Lei, Xu Gezhi
Shanghai Key Laboratory of Visual Impairment and Restoration, Eye & ENT Hospital, Fudan University, Shanghai, China.
NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.
Front Cell Dev Biol. 2020 Jul 9;8:608. doi: 10.3389/fcell.2020.00608. eCollection 2020.
Polypoidal choroidal vasculopathy (PCV) is the predominant subtype of exudative age-related macular degeneration in Asians. Although photodynamic therapy (PDT) is widely used for PCV treatment, its long-term beneficial effects are unsatisfactory. Accumulating clinical investigations suggest that combined therapy with anti-vascular endothelial growth factor (anti-VEGF) and PDT is superior to PDT monotherapy. However, the optimal time of anti-VEGF before or after PDT remains controversial, hence it needs to further explore the mechanism underlying combined therapy. PDT causes selective damage to endothelial cells, which determines its angio-occlusive efficiency, yet the impact of anti-VEGF on PDT-induced endothelial injury is unclear. Here, we found that pre- compared to post-treatment with anti-VEGF ranibizumab (rani) significantly aggravates PDT injury in the rhesus macaque choroid-retinal endothelial (RF/6A) cell line. PDT activates apoptosis, necroptosis and NLRP3 inflammasome in RF/6A cells. Pre-treatment with rani promotes PDT-caused apoptosis via triggering caspase 8-mediated extrinsic apoptosis, and caspase 8 might also play a pivotal role in the rani's function of suppressing PDT-induced necroptosis and NLRP3 inflammasome activation. Our results implicate that pre-treatment with rani may enhance the angio-occlusive efficiency of PDT and alleviate endothelial inflammatory response, which gives it a great advantage over post-treatment.
息肉样脉络膜血管病变（PCV）是亚洲人群渗出性年龄相关性黄斑变性的主要亚型。尽管光动力疗法（PDT）被广泛用于PCV治疗，但其长期有益效果并不理想。越来越多的临床研究表明，抗血管内皮生长因子（抗VEGF）与PDT联合治疗优于PDT单一疗法。然而，抗VEGF在PDT之前还是之后使用的最佳时机仍存在争议，因此需要进一步探索联合治疗的潜在机制。PDT对内皮细胞造成选择性损伤，这决定了其血管闭塞效率，但抗VEGF对PDT诱导的内皮损伤的影响尚不清楚。在此，我们发现与抗VEGF雷珠单抗（rani）治疗后相比，治疗前显著加重了恒河猴脉络膜视网膜内皮（RF/6A）细胞系中的PDT损伤。PDT激活RF/6A细胞中的凋亡、坏死性凋亡和NLRP3炎性小体。rani预处理通过触发半胱天冬酶8介导的外源性凋亡促进PDT诱导的凋亡，并且半胱天冬酶8在rani抑制PDT诱导的坏死性凋亡和NLRP3炎性小体激活的功能中可能也起关键作用。我们的结果表明，rani预处理可能提高PDT的血管闭塞效率并减轻内皮炎症反应，这使其比治疗后具有很大优势。
