Koganti Raghuram, Yadavalli Tejabhiram, Sutar Yogesh, Mallick Sudipta, Date Abhijit, Shukla Deepak
Department of Ophthalmology and Visual Sciences, University of Illinois Medical Center, 1855 W. Taylor Street, MC 648, Chicago, IL 60612, USA.
Department of Pharmaceutical Sciences, The Daniel K. Inouye College of Pharmacy, University of Hawaii Hilo, Hilo, HI 96720, USA.
iScience. 2022 Nov 26;25(12):105682. doi: 10.1016/j.isci.2022.105682. eCollection 2022 Dec 22.
Chronic inflammation of the immune privileged cornea originating from viral or nonviral conditions results in significant vision loss. Topical corticosteroids are the common treatments for corneal inflammation, but the drugs cause serious and potentially blinding side effects in the long term. Therefore, new standalone and/or synergistic anti-inflammatory therapies with lower side effects are desperately needed. Here, we show that the aromatic fatty acid phenylbutyrate (PBA) acts as a potent inhibitor of inflammation in preclinical ocular-inflammation models. PBA prevents the transcription as well as translation of pro-inflammatory cytokines by LPS and poly(I:C) via persistent inhibition of NF-κB signaling. PBA quickens the resolution of ocular inflammation in mice by decreasing corneal thickness and immune cell infiltration. More importantly, PBA can synergize with the dexamethasone to antagonize NF-κB signaling at lower drug concentrations. Our results demonstrate that PBA therapy exerts previously unreported anti-inflammatory effects in the eye and facilitates corneal healing during persistent inflammation.
源于病毒或非病毒状况的免疫赦免角膜的慢性炎症会导致严重的视力丧失。局部用皮质类固醇是治疗角膜炎症的常用药物，但长期使用这些药物会引起严重且可能致盲的副作用。因此，迫切需要新的副作用较小的独立和/或协同抗炎疗法。在此，我们表明芳香脂肪酸苯丁酸盐（PBA）在临床前眼部炎症模型中作为一种有效的炎症抑制剂发挥作用。PBA通过持续抑制NF-κB信号传导来阻止LPS和聚肌胞苷酸（poly(I:C)）诱导的促炎细胞因子的转录和翻译。PBA通过降低角膜厚度和免疫细胞浸润来加速小鼠眼部炎症的消退。更重要的是，PBA可以与地塞米松协同作用，在较低药物浓度下拮抗NF-κB信号传导。我们的结果表明，PBA疗法在眼部发挥了以前未报道的抗炎作用，并在持续性炎症期间促进角膜愈合。
