Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva
Valproic acid exerts specific cellular and molecular anti-inflammatory effects in post-operative conjunctiva
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丙戊酸在术后结膜中发挥特定的细胞和分子抗炎作用
DOI：
10.1007/s00109-018-1722-x
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
T. Wong
中科院分区：
文献类型：
--
作者：
L. Seet;L. Toh;S. N. Finger;Stephanie W. L. Chu;T. Wong
丙戊酸（VPA）是一种组蛋白脱乙酰酶抑制剂，临床上用于治疗神经系统疾病。它也可能用作抗纤维化治疗，因为它减少了术后结膜中的胶原蛋白沉积。在本研究中，我们使用结膜瘢痕小鼠模型进一步评价了VPA对术后炎症的影响。手术后立即将VPA注射到结膜下，通过活体显微镜检查时未引起任何不良组织反应，并且在免疫组织学检查中促炎性和促血管生成标志物明显减少。对处理的手术组织进行的深入分析显示，VPA选择性抑制CD 45 highF 4/80 low巨噬细胞亚群以及特异性促炎细胞因子/趋化因子（包括CXCL 1、IL-5、IL-6和IL-10）的产生，其减少≥ 2.0倍。VPA还特异性降低组织NF-кB2 p100蛋白，平均降低3.87倍。在结膜成纤维细胞上，VPA处理导致特定细胞因子（包括CCL 2、VEGF-A和IL-15）分泌减少。在存在TNF-α的情况下，VPA可抑制特异性细胞因子/趋化因子的诱导，尤其是CCL 5和VEGF-A以及NF-кB2 p100。进一步证实，VPA抑制TNF-α对NF-B报告基因转录的刺激，抑制倍数为1.51倍。这些数据表明VPA可以选择性地调节促炎细胞和分子靶点，因此可以减轻手术诱导的结膜炎症。这些和之前的研究结果表明，通过抑制炎症和纤维化的关键介质，VPA是改善涉及结膜的手术结果的有用治疗剂。VPA可抑制CD 45 highF 4/80 low巨噬细胞亚群的募集。VPA可降低治疗组织中的趋化因子和细胞因子水平。VPA选择性抑制组织NF-кB2 p100水平。VPA抑制TNF-α诱导的趋化因子、细胞因子和NF-кB2 p100表达。VPA抑制TNF-α对NF-κ B B报告基因的刺激。VPA可抑制CD 45 highF 4/80 low巨噬细胞亚群的募集。VPA可降低治疗组织中的趋化因子和细胞因子水平。VPA选择性抑制组织NF-кB2 p100水平。VPA抑制TNF-α诱导的趋化因子、细胞因子和NF-кB2 p100表达。VPA抑制TNF-α对NF-κ B B报告基因的刺激。
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 CD45highF4/80low 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. VPA inhibited recruitment of a CD45highF4/80low 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. VPA inhibited recruitment of a CD45highF4/80low 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.
DOI：
10.1152/ajprenal.00332.2011
发表时间：
2011-12-01
影响因子：
4.2
作者：
Awad, Alaa S.;Kinsey, Gilbert R.;Okusa, Mark D.
通讯作者：
Okusa, Mark D.
影响因子：
19.6
作者：
Li, Li;Huang, Liping;Sung, Sun-Sang J.;Vergis, Amy L.;Rosin, Diane L.;Rose, C. Edward, Jr.;Lobo, Peter I.;Okusa, Mark D.
通讯作者：
Okusa, Mark D.