Sun Yan, Pearlman Eric
Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Invest Ophthalmol Vis Sci. 2009 Mar;50(3):1247-54. doi: 10.1167/iovs.08-2628. Epub 2008 Oct 20.
To investigate the role of the TLR4/MD-2 antagonist eritoran tetrasodium in a murine model of contact lens-associated corneal infiltrates.
C57BL/6 mouse corneas were abraded and treated with eritoran tetrasodium or placebo, either before or after stimulation with either LPS, the TLR2 ligand Pam(3)Cys, or antibiotic-killed Pseudomonas aeruginosa. A 2-mm punch from a silicon hydrogel contact lens was used to cover the corneal surface throughout the inhibition and stimulation period. Corneal infiltrates were detected by in vivo confocal microscopy and by immunohistochemistry for neutrophils. The effect of eritoran tetrasodium on stimulated human corneal epithelial cells (HCECs), macrophages, and neutrophils was also assessed.
Eritoran tetrasodium significantly inhibited CXC chemokine production in the cornea and development of corneal infiltrates, specifically neutrophils, in response to stimulation with LPS (TLR4), but not Pam(3)Cys (TLR2). When the antagonist was applied after LPS stimulation, neutrophil infiltration was also inhibited, although a higher concentration was needed. Furthermore, IL-8 production by TLR4- but not TLR2-stimulated HCECs, macrophages and neutrophils was also significantly reduced. Corneal inflammation induced by P. aeruginosa in the presence of tobramycin was found to be dependent on expression of TLR4 and MD-2 and is inhibited by eritoran tetrasodium.
Eritoran tetrasodium is a highly effective antagonist of TLR4/MD-2-dependent corneal inflammation.
研究Toll样受体4（TLR4）/髓样分化蛋白2（MD-2）拮抗剂依替膦酸四钠在小鼠隐形眼镜相关性角膜浸润模型中的作用。
对C57BL/6小鼠角膜进行擦伤处理，在使用脂多糖（LPS）、TLR2配体Pam(3)Cys或抗生素灭活的铜绿假单胞菌刺激之前或之后，用依替膦酸四钠或安慰剂进行处理。在整个抑制和刺激期，使用直径2毫米的硅水凝胶隐形眼镜打孔片覆盖角膜表面。通过体内共聚焦显微镜和中性粒细胞免疫组织化学检测角膜浸润情况。还评估了依替膦酸四钠对受刺激的人角膜上皮细胞（HCEC）、巨噬细胞和中性粒细胞的影响。
依替膦酸四钠可显著抑制角膜中CXC趋化因子的产生以及角膜浸润（特别是中性粒细胞）的形成，该浸润是对LPS（TLR4）刺激的反应，但对Pam(3)Cys（TLR2）刺激无此作用。当在LPS刺激后应用拮抗剂时，尽管需要更高的浓度，但中性粒细胞浸润也受到抑制。此外，TLR4而非TLR2刺激的HCEC、巨噬细胞和中性粒细胞产生的白细胞介素-8也显著减少。发现妥布霉素存在下铜绿假单胞菌诱导的角膜炎症依赖于TLR4和MD-2的表达，并受到依替膦酸四钠的抑制。
依替膦酸四钠是TLR4/MD-2依赖性角膜炎症的高效拮抗剂。
