AyuVis Research Inc., Fort Worth, TX 76107, USA.
The North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Cells. 2024 Aug 17;13(16):1371. doi: 10.3390/cells13161371.
Retinopathy of prematurity (ROP) has a dual-phase disease pathology; in phase 1, hyperoxia-induced vaso-obliteration occurs in the retinal vasculature due to increased oxidative stress (OS) and inflammation, followed by phase 2, where hypoxia increases the overproduction of growth factors, inducing retinal neovascularization. Toll-like receptor 2 and -4 (TLR2 and TLR4) overactivation, hyper-inflammation, macrophages, and neutrophil infiltration contribute to the developing ROP. AVR-121 and AVR-123 are novel classes of small-molecule dual inhibitors of TLR2/4 tested in a human leukemia monocytic cell line (THP-1) and cord-blood-derived mononuclear cells (CBMCs). Both compounds inhibited TLR2/4 signaling-related inflammatory cytokines in THP-1 cells and inhibited VEGF-induced neovascularization in human retinal endothelial cells (HRECs), which are hallmarks of ROP. In an oxygen-induced retinopathy (OIR) murine model, the intraperitoneal injection of AVR-123 in the hyperoxia phase (P7-P12) or a nanosuspension eyedrop of AVR-123 in the hypoxic phase (P12-P17) significantly reduced vaso-obliteration, angiogenesis, and inflammatory cytokine profiles while not inhibiting the necessary growth factor VEGF in the juvenile mouse eyes. The results are consistent with our hypothesis that targeting the dual TLR2/4 pathway will reduce inflammation, angiogenesis, and vaso-obliteration in vitro and in vivo and reduce cytotoxic immune cells. AVR-123 has the potential to be developed as a therapy for ROP.
早产儿视网膜病变（ROP）具有双相疾病病理学；在第 1 相，由于氧化应激（OS）和炎症增加，视网膜血管中的高氧诱导血管闭塞，随后在第 2 相，缺氧会增加生长因子的过度产生，诱导视网膜新生血管形成。Toll 样受体 2 和 -4（TLR2 和 TLR4）过度激活、过度炎症、巨噬细胞和中性粒细胞浸润导致 ROP 的发展。AVR-121 和 AVR-123 是新型 TLR2/4 小分子双重抑制剂，在人白血病单核细胞系（THP-1）和脐带血来源的单核细胞（CBMC）中进行了测试。这两种化合物均抑制了 THP-1 细胞中 TLR2/4 信号相关的炎症细胞因子，并抑制了人视网膜内皮细胞（HRECs）中 VEGF 诱导的新生血管形成，这是 ROP 的标志。在氧诱导的视网膜病变（OIR）小鼠模型中，在高氧相（P7-P12）中腹腔注射 AVR-123 或在低氧相（P12-P17）中用 AVR-123 纳米混悬滴眼剂治疗，可显著减少血管闭塞、血管生成和炎症细胞因子谱，同时不抑制幼年小鼠眼中必需的生长因子 VEGF。结果与我们的假设一致，即靶向双重 TLR2/4 途径将减少体外和体内的炎症、血管生成和血管闭塞，并减少细胞毒性免疫细胞。AVR-123 有可能被开发为 ROP 的治疗方法。
