Department of Pharmacology, Kyoto Pharmaceutical University, 5 Nakauchi, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Exp Eye Res. 2013 Aug;113:74-9. doi: 10.1016/j.exer.2013.05.015. Epub 2013 May 28.
It has been reported that chymase activity was increased in allergic conjunctivitis patients and this activity was correlated with the severity of the disease. However, the precise roles of chymase in allergic conjunctivitis are unclear, and whether chymase inhibitors are effective for allergic conjunctivitis has not been reported even in experimental animal models. In this study, the roles of chymase in the pathogenesis were evaluated using a selective chymase inhibitor, ONO-WH-236, in a guinea pig model of allergic conjunctivitis induced by cedar pollen. Sensitized guinea pigs were challenged by the pollen, followed by assessing redness and edema in the conjuntiva, and counting the frequency of eye scratching as an itch-associated response. Treatment with the ONO-WH-236 (40 and 80 mg/kg, p.o.) dose-dependently inhibited the induction of redness, edema and scratching behavior. An anti-histaminic drug, ketotifen (3 mg/kg, p.o.), also significantly inhibited conjunctivitis symptoms. Chymase activity was increased in ophthalmic lavage fluid immediately after the pollen challenge. The increase in chymase activity was inhibited by in vivo treatment with ONO-WH-236. Interestingly, increased histamine in the ophthalmic lavage fluid immediately after the challenge was also inhibited by the chymase inhibitor. Administration of human recombinant chymase by eye dropping (0.09 and 0.9 μg/eye) dose-dependently induced scratching behavior, which was inhibited by not only ONO-WH-236 but also ketotifen; however, chymase administration induced only weak redness in the conjunctiva, which was resistant to treatment with anti-histaminic drugs. In conclusion, it was suggested that chymase was released from mast cells after antigen challenge, followed by the induction of conjunctivitis symptoms through histamine release from mast cells. Thus, chymase could be a potential target for pharmacotherapy for allergic conjunctivitis.
据报道，糜酶活性在变应性结膜炎患者中增加，并且这种活性与疾病的严重程度相关。然而，糜酶在变应性结膜炎中的确切作用尚不清楚，即使在实验动物模型中也没有报道糜酶抑制剂对变应性结膜炎是否有效。在这项研究中，我们使用一种选择性糜酶抑制剂 ONO-WH-236 在豚鼠草花粉诱导的变应性结膜炎模型中评估了糜酶在发病机制中的作用。致敏豚鼠通过花粉进行挑战，随后评估结膜的红肿和水肿程度，并计算搔抓眼睛的频率作为瘙痒相关反应。ONO-WH-236（40 和 80mg/kg，po）剂量依赖性地抑制了红肿、水肿和搔抓行为的诱导。一种抗组胺药酮替芬（3mg/kg，po）也显著抑制了结膜炎症状。在花粉挑战后立即，眼灌洗液中的糜酶活性增加。ONO-WH-236 的体内治疗抑制了糜酶活性的增加。有趣的是，在挑战后立即，眼灌洗液中组胺的增加也被糜酶抑制剂抑制。通过滴眼（0.09 和 0.9μg/眼）给予人重组糜酶剂量依赖性地诱导搔抓行为，该行为不仅被 ONO-WH-236 抑制，而且被酮替芬抑制；然而，糜酶给药仅引起结膜的轻微红肿，该红肿对抗组胺药物治疗有抗性。总之，研究结果提示，抗原挑战后糜酶从肥大细胞中释放出来，随后通过肥大细胞释放组胺诱导结膜炎症状。因此，糜酶可能是变应性结膜炎药物治疗的潜在靶点。
