Davis K L, Conners M S, Dunn M W, Schwartzman M L
Department of Pharmacology, New York Medical College, Valhalla.
Invest Ophthalmol Vis Sci. 1992 Feb;33(2):291-7.
Two biologically active cytochrome P-450 arachidonate metabolites previously were characterized: 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(R)-HETE) and 12(R)-hydroxy-5,8,14-eicosatrienoic acid (12(R)-DH-HETE), which are endogenously formed in the corneal epithelium. The functional activity of these novel metabolites mimics changes observed in hypoxic corneas. Therefore, the effect of hypoxic stress was examined on metabolite formation in rabbits fitted with polymethylmethacrylate contact lenses. Although applied lenses fit tightly to the rabbit cornea, mechanical irritation also may contribute to the ocular response. Contact lens-induced hypoxic stress stimulated endogenous formation of both 12(R)-HETE (a sodium, potassium adenosine triphosphatase inhibitor) and 12(R)-DH-HETE (a vasodilatory, chemotactic, and angiogenic factor) in a time-dependent manner. After 4 hr of contact lens wear, a 21-fold increase in endogenous 12(R)-HETE formation concomitant with an increase in corneal thickness was observed. After prolonged contact lens wear (144 hr), a 23-fold increase in endogenous 12(R)-DH-HETE formation was found, corresponding with the appearance of a marked conjunctival inflammation characterized by corneal neovascularization. The increased formation of these compounds was associated with time-dependent changes in corneal endothelial morphology. The ability of 12(R)-HETE and 12(R)-DH-HETE to mediate the clinical signs of corneal hypoxia suggest these metabolites may be potential mediators of contact lens complications that followed conditions of hypoxic stress and possibly mechanical irritation in this model.
此前已鉴定出两种具有生物活性的细胞色素P-450花生四烯酸代谢产物：12(R)-羟基-5,8,10,14-二十碳四烯酸（12(R)-HETE）和12(R)-羟基-5,8,14-二十碳三烯酸（12(R)-DH-HETE），它们在内角膜上皮中内源性形成。这些新型代谢产物的功能活性模拟了在缺氧角膜中观察到的变化。因此，研究了缺氧应激对佩戴聚甲基丙烯酸甲酯隐形眼镜的兔子代谢产物形成的影响。尽管所佩戴的隐形眼镜与兔子角膜紧密贴合，但机械刺激也可能导致眼部反应。隐形眼镜诱导的缺氧应激以时间依赖性方式刺激了12(R)-HETE（一种钠钾腺苷三磷酸酶抑制剂）和12(R)-DH-HETE（一种血管舒张、趋化和血管生成因子）的内源性形成。佩戴隐形眼镜4小时后，观察到内源性12(R)-HETE形成增加了21倍，同时角膜厚度增加。长时间佩戴隐形眼镜（144小时）后，发现内源性12(R)-DH-HETE形成增加了23倍，这与以角膜新生血管形成为特征的明显结膜炎症的出现相对应。这些化合物形成的增加与角膜内皮形态的时间依赖性变化有关。12(R)-HETE和12(R)-DH-HETE介导角膜缺氧临床症状的能力表明，在该模型中，这些代谢产物可能是缺氧应激和可能的机械刺激条件下隐形眼镜并发症的潜在介质。
