Bora Nalini S, Sohn Jeong-Hyeon, Bora Puran S, Kaplan Henry J, Kulkarni Prasad
Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Center, School of Medicine, University of Louisville, 40202, USA.
Ocul Immunol Inflamm. 2005 Apr-Jun;13(2-3):183-9. doi: 10.1080/09273940590928643.
Inflammation, in general, causes the release of a variety of inflammatory mediators that in turn induce cyclooxygenase (COX) 2, nitric oxide synthase (iNOS) and 5-lipoxygense (LP) synthesis, producing large amounts of inflammatory prostaglandins (PG), nitric oxide (NO), and leukotriene (LT) B4. Therefore, inhibition of these enzymes may abrogate intraocular inflammation in experimental autoimmune anterior uveitis (EAAU).
Lewis rats were immunized with melanin-associated antigen (MAA) isolated from bovine iris and ciliary body. These animals were divided into three groups. The first group of rats received subcutaneous injection of COX 2 inhibitor CS 236 at different time points. The second and third groups of animals received subcutaneous aminoguanidine (AG), an iNOS inhibitor, and nordihydroguaiaretic acid (NDGA), a 5-LP inhibitor, respectively. Control animals received vehicle. Rat eyes were examined daily by slit-lamp biomicroscopy from Day 7 to 30 post injection for uveitis. Animals were also sacrificed at various time points for histologic analysis.
Control animals developed severe EAAU in both eyes. The disease started in these animals on Day 12 post immunization and lasted for ten days. Interestingly, CS 236, a potent COX 2 inhibitor, completely abrogated EAAU when the animals were treated daily from the Day 0 to 14 or Day 0 to 20 after MAA injection. Furthermore, daily CS 236 treatment after the onset of EAAU (Day 14-20) significantly reduced the severity (both clinical and histologic) of EAAU and shortened the duration of disease. iNOS inhibitor (AG) and 5-LP inhibitor (NDGA) partially attenuated EAAU.
Our results show that EAAU was partially attenuated by AG and NDGA. Interestingly, CS 236, a potent COX 2 inhibitor, completely inhibited EAAU in male Lewis rats most likely by inhibiting the initial phase and onset of the disease.
一般来说，炎症会导致多种炎症介质的释放，这些炎症介质反过来会诱导环氧化酶（COX）2、一氧化氮合酶（iNOS）和5-脂氧合酶（LP）的合成，从而产生大量的炎症性前列腺素（PG）、一氧化氮（NO）和白三烯（LT）B4。因此，抑制这些酶可能会消除实验性自身免疫性前葡萄膜炎（EAAU）中的眼内炎症。
用从牛虹膜和睫状体中分离出的黑色素相关抗原（MAA）免疫Lewis大鼠。这些动物被分为三组。第一组大鼠在不同时间点皮下注射COX 2抑制剂CS 236。第二组和第三组动物分别皮下注射iNOS抑制剂氨基胍（AG）和5-LP抑制剂去甲二氢愈创木酸（NDGA）。对照组动物注射赋形剂。从注射后第7天到第30天，每天用裂隙灯生物显微镜检查大鼠眼睛的葡萄膜炎情况。在不同时间点处死动物进行组织学分析。
对照组动物双眼均发生严重的EAAU。这些动物在免疫后第12天开始发病，持续10天。有趣的是，强效COX 2抑制剂CS 236在动物于MAA注射后第0天至14天或第0天至20天每天接受治疗时，完全消除了EAAU。此外，在EAAU发病后（第14 - 20天）每天用CS 236治疗可显著降低EAAU的严重程度（临床和组织学方面）并缩短疾病持续时间。iNOS抑制剂（AG）和5-LP抑制剂（NDGA）部分减轻了EAAU。
我们的结果表明，AG和NDGA部分减轻了EAAU。有趣的是，强效COX 2抑制剂CS 236最有可能通过抑制疾病的初始阶段和发病，完全抑制了雄性Lewis大鼠的EAAU。
