He Jiucheng, Bazan Nicolas G, Bazan Haydee E P
Department of Ophthalmology and Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, LA 70112, USA.
Arch Ophthalmol. 2006 Jan;124(1):70-8. doi: 10.1001/archopht.124.1.70.
To evaluate the effect of LAU0901 (2,4,6-trimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester), a novel platelet-activating factor (PAF) receptor antagonist, on a rabbit model of severe corneal alkali injury.
Adult New Zealand albino rabbits were anesthetized and the right eyes were injured with 2N sodium hydroxide for 60 seconds using a 12-mm plastic well, then rinsed. After the injury, 10 rabbits were treated topically with LAU0901 every 2 hours 4 times per day and received a subconjunctival injection of 200 microL of LAU0901 once per week and 10 rabbits were treated with vehicle the same way. Over the course of 4 weeks, the corneas were examined daily by slitlamp microscopy and corneal ulcers were graded with a clinical scoring system. Ten additional rabbits were treated as described but 1 rabbit from each group was killed at 1, 3, 7, 14, or 21 days after injury. The corneas were processed for histopathologic and immunofluorescence examination.
Persistent epithelial defects were present in both groups from day 5 postinjury, but from day 9 through day 25, the average clinical scores of both epithelial defects and stromal ulcerations in the vehicle-treated eyes were significantly higher than those in the LAU0901-treated eyes (P<.01). By day 28, 90% of the eyes in the vehicle-treated group perforated, while only 20% of the eyes in the LAU0901-treated group developed deep ulceration and none were perforated. Histologic examination showed that the corneas treated with LAU0901 for 4 weeks were completely reepithelialized, with fewer inflammatory polymorphonuclear leukocytes and more repair fibroblasts (myofibroblasts) in the stroma as compared with those treated with vehicle.
LAU0901 inhibits corneal ulceration and perforation in a severe alkali-burn model in the rabbit. In the cornea, PAF is a strong inflammatory mediator, a chemotactic to inflammatory polymorphonuclear leukocytes, and an inducer of several proteases that degrade the extracellular matrix. Clinical Relevance The inhibition of PAF action by LAU0901 could be important in the immediate and intermediate treatment of chemical injuries to preserve the integrity of the cornea.
评估新型血小板活化因子（PAF）受体拮抗剂LAU0901（2,4,6-三甲基-1,4-二氢吡啶-3,5-二羧酸酯）对兔重度角膜碱烧伤模型的作用。
成年新西兰白化兔麻醉后，用12毫米塑料孔板将右眼暴露于2N氢氧化钠中60秒致伤，然后冲洗。伤后，10只兔每天4次每2小时局部给予LAU0901，并每周1次结膜下注射200微升LAU0901；另10只兔以同样方式给予赋形剂。在4周的过程中，每天用裂隙灯显微镜检查角膜，并用临床评分系统对角膜溃疡进行分级。另外10只兔按上述方法处理，但每组在伤后1、3、7、14或21天处死1只兔。对角膜进行组织病理学和免疫荧光检查。
伤后第5天两组均出现持续性上皮缺损，但从第9天至第25天，赋形剂处理组的上皮缺损和基质溃疡的平均临床评分显著高于LAU0901处理组（P<0.01）。至第28天，赋形剂处理组90%的眼发生穿孔，而LAU0901处理组仅20%的眼出现深度溃疡，无眼穿孔。组织学检查显示，与赋形剂处理组相比，LAU0901处理4周的角膜完全重新上皮化，基质中炎性多形核白细胞较少，修复性成纤维细胞（肌成纤维细胞）较多。
LAU0901可抑制兔重度碱烧伤模型中的角膜溃疡和穿孔。在角膜中，PAF是一种强大的炎症介质，对炎性多形核白细胞具有趋化作用，并且是几种降解细胞外基质的蛋白酶的诱导剂。临床意义：LAU0901对PAF作用的抑制在化学伤的即刻和中期治疗中对于维持角膜完整性可能具有重要意义。
