Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 6.644 Basic Science Building, 301 University Blvd., Galveston, TX 77555-0647, USA.
Exp Eye Res. 2010 May;90(5):555-63. doi: 10.1016/j.exer.2010.01.012. Epub 2010 Feb 4.
Chronic inflammatory diseases such as autoimmune and bacterial infections are associated with an elevated risk of ocular inflammation. Ciliary epithelial cells that play an important role in maintaining aqueous humor dynamics and homeostasis of anterior segment of eye are continuously exposed to inflammatory markers during infections and injury. Lipopolysacchharide (LPS), a Gram-negative bacterial endotoxin, dysregulates aqueous humor (AqH) homeostasis by inducing inflammatory changes. We have investigated how inhibition of a polyol pathway enzyme, aldose reductase (AR), alters LPS-induced inflammatory changes in human non-pigmented ciliary epithelial cells (hNPECs). The stimulation of hNPECs with LPS (1 microg/ml) caused increased secretion of inflammatory markers such as PGE(2) and NO in the culture medium as well as increased expression of COX-2 and iNOS proteins in cell extracts. LPS also increased phosphorylation of MAPKs (ERK1/2) and SAPK/JNK and activation of redox-sensitive transcription factors NF-kappaB and AP-1 in hNPECs and inhibition of AR by zopolrestat and sorbinil ameliorated these changes. Further, LPS-induced decrease in the expression of Na/K-ATPase in hNPECs was restored by AR inhibitors. Similar results were observed in ciliary bodies of LPS-injected rats. Taken together, our results suggest that AR plays an important role in the LPS-induced inflammatory changes in hNPECs and that inhibition of AR could be a novel therapeutic approach for ocular inflammation.
慢性炎症性疾病，如自身免疫性和细菌性感染，与眼部炎症的风险增加有关。睫状上皮细胞在维持房水动力学和眼前节的内稳态方面起着重要作用，在感染和损伤过程中不断暴露于炎症标志物中。脂多糖（LPS）是革兰氏阴性细菌内毒素，通过诱导炎症变化，扰乱房水（AqH）的内稳态。我们研究了抑制多元醇途径酶醛糖还原酶（AR）如何改变 LPS 诱导的人非色素睫状上皮细胞（hNPECs）中的炎症变化。用 LPS（1μg/ml）刺激 hNPECs 会导致培养物中炎症标志物如 PGE（2）和 NO 的分泌增加，以及细胞提取物中 COX-2 和 iNOS 蛋白的表达增加。LPS 还增加了 MAPKs（ERK1/2）和 SAPK/JNK 的磷酸化以及氧化还原敏感转录因子 NF-kappaB 和 AP-1 在 hNPECs 中的激活，而 AR 的抑制物唑泊司他和 sorbinil 改善了这些变化。此外，LPS 诱导的 hNPECs 中 Na/K-ATPase 表达的降低也被 AR 抑制剂所恢复。在 LPS 注射大鼠的睫状体内也观察到了类似的结果。总之，我们的结果表明，AR 在 LPS 诱导的 hNPECs 炎症变化中起着重要作用，抑制 AR 可能是治疗眼部炎症的一种新方法。
