Ubels J L, Dennis M H, Mitchell J H, Wiley L A, Curley R W
Department of Ophthalmology, University of Pittsburgh School of Medicine, PA, USA.
Curr Eye Res. 1995 Dec;14(12):1115-24. doi: 10.3109/02713689508995818.
Previous studies of topical retinoic acid for treatment of ocular surface disease met with limited success due to instability and irritancy of the retinoid and lack of efficacy in keratoconjunctivitis sicca. There has, however, been continued interest in the treatment of mucin deficiency and cicatrizing conjunctival diseases, such as ocular cicatricial pemphigoid (OCP), topically with retinoids. In this study the biological activity of stable, water-soluble, synthetic retinoid, N-(4-hydroxyphenyl) retinamide-O-glucuronide (4-HPROG) was investigated in vivo and in vitro using conjunctival and corneal epithelium and fibroblasts. Vitamin A-deficient rabbits with stage 3-4 corneal xerosis and squamous metaplasia confirmed by conjunctival impression cytology were treated with topical 0.1% 4-HPROG in an artificial tear vehicle for 3 weeks. Impression cytology was repeated at 2 and 3 weeks and at 3 weeks conjunctival biopsies were fixed for histology. Growth curves were generated using conjunctival fibroblasts of rabbits and humans (normals and patients with cicatrizing conjunctival disease including OCP and Stevens-Johnson syndrome) cultured in the 10(-8)-10(-6) M 4-HPROG. In vivo, corneal xerosis cleared in three days. A normal conjunctival epithelium was restored by 2 weeks and goblet cells were present by 3 wk, with no change in vehicle-treated controls. No ocular irritation occurred. In vitro, 10(-6) M 4-HPROG inhibits growth of rabbit conjunctival fibroblasts. The retinoid had no effect on proliferation of conjunctival fibroblasts from normal humans but the doubling time of cells from patients with OCP increased significantly, from 50.9 +/- 10.01 h (control) to 61.5 +/- 8.95 h (retinoid). Proliferation of conjunctival fibroblasts from a patient with Stevens-Johnson syndrome was also inhibited. N-(4-hydroxyphenyl) retinamide-O-glucuronide is biologically active and merits further study to determine its efficacy in controlling conjunctival fibrosis and treating ocular surface squamous metaplasia.
以往关于局部应用维甲酸治疗眼表疾病的研究由于维甲酸的不稳定性、刺激性以及在干燥性角结膜炎中缺乏疗效而成效有限。然而，对于黏液缺乏和瘢痕性结膜疾病，如眼瘢痕性类天疱疮（OCP），局部应用维甲酸进行治疗一直备受关注。在本研究中，使用结膜和角膜上皮细胞以及成纤维细胞，在体内和体外研究了稳定的、水溶性合成维甲酸N-(4-羟苯基)视黄酰胺-O-葡萄糖醛酸（4-HPROG）的生物活性。通过结膜印片细胞学确诊为3-4期角膜干燥症和鳞状化生的维生素A缺乏兔，用含0.1% 4-HPROG的人工泪液载体局部治疗3周。在第2周和第3周重复印片细胞学检查，并在第3周固定结膜活检组织进行组织学检查。使用在10(-8)-10(-6) M 4-HPROG中培养的兔和人（正常人和患有瘢痕性结膜疾病包括OCP和史蒂文斯-约翰逊综合征的患者）的结膜成纤维细胞绘制生长曲线。在体内，角膜干燥症在三天内消退。2周时恢复正常结膜上皮，3周时出现杯状细胞，而用载体处理的对照组无变化。未发生眼部刺激。在体外，10(-6) M 4-HPROG抑制兔结膜成纤维细胞的生长。该维甲酸对正常人结膜成纤维细胞的增殖没有影响，但OCP患者细胞的倍增时间显著增加，从50.9±10.01小时（对照）增加到61.5±8.95小时（维甲酸）。史蒂文斯-约翰逊综合征患者的结膜成纤维细胞增殖也受到抑制。N-(4-羟苯基)视黄酰胺-O-葡萄糖醛酸具有生物活性，值得进一步研究以确定其在控制结膜纤维化和治疗眼表鳞状化生方面的疗效。
