Ocular Therapeutics and Drug Delivery, Singapore Eye Research Institute, The Academia, 20 College Road, Singapore, 169856, Singapore.
Department of Ophthalmology, Yong Loo Lin Sc hool of Medicine, National University of Singapore, Singapore, Singapore.
J Mol Med (Berl). 2019 Jan;97(1):63-75. doi: 10.1007/s00109-018-1722-x. Epub 2018 Nov 19.
Valproic acid (VPA) is a histone deacetylase inhibitor used clinically for neurological disorders. It is also potentially useful as anti-fibrotic therapy as it reduced collagen deposition in the post-operative conjunctiva. In this study, we further evaluated the effects of VPA on post-operative inflammation using the mouse model of conjunctival scarring. VPA, injected into the subconjunctiva immediately after surgery, did not cause any adverse tissue response when examined by live microscopy and produced an apparent reduction of proinflammatory and proangiogenic markers in immunohistological examinations. In-depth analyses of the treated operated tissues revealed that VPA selectively inhibited the CD45F4/80 macrophage subset as well as the production of specific proinflammatory cytokines/ chemokines, including CXCL1, IL-5, IL-6, and IL-10 which were reduced by ≥ 2.0-fold. VPA also specifically reduced tissue NF-кB2 p100 protein by mean 3.87-fold. On conjunctival fibroblasts, VPA treatment resulted in decreased secretion of specific cytokines, including CCL2, VEGF-A, and IL-15. In the presence of TNF-α, VPA inhibited the induction of specific cytokines/chemokines, notably CCL5 and VEGF-A, as well as NF-кB2 p100. In corroboration, VPA suppressed TNF-α stimulation of NF-кB reporter transcription by 1.51-fold. These data indicate that VPA can modulate both proinflammatory cellular and molecular targets in a selective manner and may therefore attenuate surgery-induced conjunctival inflammation. These and previous findings suggest that, by suppressing key mediators of both inflammation and fibrosis, VPA is a useful therapeutic for improving surgical outcome involving the conjunctiva. KEY MESSAGES: VPA inhibited recruitment of a CD45F4/80 macrophage subset. VPA reduced chemokine and cytokine levels in treated tissues. VPA selectively suppressed tissue NF-кB2 p100 levels. VPA suppressed TNF-α induction of chemokines, cytokines and NF-кB2 p100 expression. VPA suppressed TNF-α stimulation of NF-кB reporter.
丙戊酸（VPA）是一种组蛋白去乙酰化酶抑制剂，临床上用于治疗神经紊乱。它也可能作为抗纤维化治疗方法，因为它减少了术后结膜的胶原沉积。在这项研究中，我们使用结膜瘢痕形成的小鼠模型进一步评估了 VPA 对术后炎症的影响。VPA 在手术后立即注射到结膜下，在活体显微镜下检查时没有引起任何不良的组织反应，并在免疫组织化学检查中明显减少了促炎和促血管生成标志物。对治疗的手术组织进行深入分析表明，VPA 选择性抑制 CD45F4/80 巨噬细胞亚群以及特定促炎细胞因子/趋化因子的产生，包括 CXCL1、IL-5、IL-6 和 IL-10，这些因子的减少幅度≥2.0 倍。VPA 还特异性地将组织 NF-кB2 p100 蛋白减少了 3.87 倍。在结膜成纤维细胞上，VPA 处理导致特定细胞因子的分泌减少，包括 CCL2、VEGF-A 和 IL-15。在 TNF-α存在的情况下，VPA 抑制了特定细胞因子/趋化因子的诱导，特别是 CCL5 和 VEGF-A，以及 NF-кB2 p100。作为佐证，VPA 抑制了 TNF-α刺激的 NF-кB 报告基因转录 1.51 倍。这些数据表明，VPA 可以以选择性的方式调节促炎细胞和分子靶标，并可能因此减轻手术引起的结膜炎症。这些和以前的发现表明，通过抑制炎症和纤维化的关键介质，VPA 是一种用于改善涉及结膜的手术结果的有用治疗方法。关键信息：VPA 抑制了 CD45F4/80 巨噬细胞亚群的募集。VPA 降低了治疗组织中的趋化因子和细胞因子水平。VPA 选择性地抑制组织 NF-кB2 p100 水平。VPA 抑制了 TNF-α诱导的趋化因子、细胞因子和 NF-кB2 p100 表达。VPA 抑制了 TNF-α刺激的 NF-кB 报告基因。
