Suphapimol Varaporn, Liu Yu-Han, Prato Sandro, Karnowski Alexander, Hardy Charles, Morelli Adriana Baz, Jayasimhan Abhirup, Deliyanti Devy, Wilkinson-Berka Jennifer L
Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Parkville, VIC, Australia.
CSL Limited, Melbourne, VIC, Australia.
J Inflamm (Lond). 2025 Feb 11;22(1):6. doi: 10.1186/s12950-025-00431-3.
Damage to the retinal vasculature is a major cause of vision loss and is influenced by a pro-inflammatory environment within retinal tissue. Alpha-1 antitrypsin (AAT) is a potent inhibitor of serine proteases and has anti-inflammatory properties. We hypothesised that AAT could reduce inflammation and vasculopathy in neovascular retinopathies including oxygen-induced retinopathy (OIR).
Litters of C57BL/6J mice were randomised to develop OIR by exposure to high oxygen between postnatal days 7 to 12 resulting in vaso-obliteration (phase I OIR), and then room air from postnatal days 12 to 18 resulting in neovascularisation (phase II OIR). Control mice were exposed to room air. Separate cohorts of mice were administered control vehicle or human AAT (120 mg/kg) by intraperitoneal injection every second day in phase I or phase II OIR.
In phase I OIR, plasma levels of AAT were reduced compared to room air controls, and AAT treatment reduced vaso-obliteration. In phase II OIR, AAT treatment influenced inflammation by reducing the density of ionised calcium binding adaptor protein 1 + cells (microglia/macrophages) and modulating their cell process length and reducing mRNA levels of tumour necrosis factor and monocyte chemoattractant protein-1, but not interleukin-1b and interleukin-6 in retina. Furthermore, AAT treatment reduced retinal neovascularisation, gliosis, vascular endothelial growth factor mRNA and protein expression, and vascular leakage, compared to OIR controls.
This research demonstrates the vasculo-protective actions of AAT, and thereby the potential of AAT as a therapeutic option for neovascular retinopathies.
视网膜血管损伤是视力丧失的主要原因，且受视网膜组织内促炎环境的影响。α1抗胰蛋白酶（AAT）是一种有效的丝氨酸蛋白酶抑制剂，具有抗炎特性。我们假设AAT可以减轻包括氧诱导性视网膜病变（OIR）在内的新生血管性视网膜病变中的炎症和血管病变。
将C57BL/6J小鼠幼崽随机分组，在出生后第7至12天暴露于高氧环境中以诱导OIR，导致血管闭塞（OIR第一阶段），然后在出生后第12至18天置于空气中，导致新生血管形成（OIR第二阶段）。对照小鼠暴露于空气中。在OIR第一阶段或第二阶段，每隔一天通过腹腔注射给另一组小鼠施用对照载体或人AAT（120mg/kg）。
在OIR第一阶段，与空气对照组相比，AAT的血浆水平降低，且AAT治疗减少了血管闭塞。在OIR第二阶段，AAT治疗通过降低离子钙结合衔接蛋白1+细胞（小胶质细胞/巨噬细胞）的密度、调节其细胞突起长度以及降低视网膜中肿瘤坏死因子和单核细胞趋化蛋白-1的mRNA水平来影响炎症，但对白细胞介素-1β和白细胞介素-6无影响。此外，与OIR对照组相比，AAT治疗减少了视网膜新生血管形成、胶质增生、血管内皮生长因子mRNA和蛋白表达以及血管渗漏。
本研究证明了AAT的血管保护作用，从而表明AAT作为新生血管性视网膜病变治疗选择的潜力。
