Evaluation of a novel combination of TRAM-34 and ascorbic acid for the treatment of corneal fibrosis in vivo.
Evaluation of a novel combination of TRAM-34 and ascorbic acid for the treatment of corneal fibrosis in vivo.
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TRAM-34 和抗坏血酸的新型组合在体内治疗角膜纤维化的评价。
DOI：
10.1371/journal.pone.0262046
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Mohan RR
中科院分区：
文献类型：
--
作者：
Fuchs AA;Balne PK;Giuliano EA;Sinha NR;Mohan RR
角膜损伤和异常伤口愈合通常导致角膜纤维化和随后的视力丧失。中电导钙调蛋白/钙激活K+通道（KCa3.1）已被证明可通过上调转化生长因子β（TGFβ）促进非眼部和眼部组织的纤维化。TRAM-34是KCa 3.1的选择性抑制剂，并通过下调TGFβ诱导的基质成纤维细胞向肌成纤维细胞的转分化来减少纤维化。已证明抗坏血酸通过抗VEGF和抗MMP机制有效促进角膜上皮再生和减少新生血管形成。本研究使用已建立的体内兔模型并进行临床眼部检查，评价了TRAM-34（25μM）和抗坏血酸（10%）局部治疗角膜纤维化的新型组合的耐受性和疗效。在研究终点，通过组织病理学、免疫荧光和定量实时PCR评价所有角膜中的角膜纤维化标志物。根据改良的McDonald Shadduck评分，滴眼液治疗的眼睛显示出临床结果显着改善，Fantes评分的临床浑浊减少，以及中央角膜厚度（CCT）减少。在细胞和分子水平上，与未处理的眼睛相比，滴眼液处理还显著降低了α平滑肌肌动蛋白（α-SMA）mRNA和蛋白、胶原III mRNA和纤连蛋白mRNA的表达。我们的研究表明，测试的新型双峰滴眼液耐受性良好，并有效地减少兔体内角膜纤维化/混浊。
Corneal injury and aberrant wound healing commonly result in corneal fibrosis and subsequent vision loss. Intermediate-conductance calmodulin/calcium-activated K+ channels (KCa3.1) have been shown to promote fibrosis in non-ocular and ocular tissues via upregulation of transforming growth factor beta (TGFβ). TRAM-34 is a selective inhibitor of KCa3.1 and reduces fibrosis by downregulation of TGFβ-induced transdifferentiation of stromal fibroblasts to myofibroblasts. Ascorbic acid has been demonstrated to be effective in promoting corneal re-epithelialization and reduction of neovascularization via anti-VEGF and anti-MMP mechanisms. This study evaluates tolerability and efficacy of a novel combination of TRAM-34 (25μM) and ascorbic acid (10%) topical treatment for corneal fibrosis using an established in vivo rabbit model and conducting clinical eye examinations. Markers of corneal fibrosis were evaluated in all corneas at study endpoint via histopathology, immunofluorescence, and quantitative real-time PCR. The eyedrop treated eyes showed significantly improved clinical outcomes based on modified McDonald Shadduck scores, reduction of clinical haze on Fantes scores, and reduction of central corneal thickness (CCT). At cellular and molecular levels, eyedrop treatment also significantly reduced expression of alpha smooth muscle actin (α-SMA) mRNA and protein, collagen III mRNA, and fibronectin mRNA compared to non-treated eyes. Our study suggests that a tested new bimodal eyedrop is well tolerated and effectively reduces corneal fibrosis/haze in rabbits in vivo.
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影响因子：
4.4
作者：
Gupta S;Fink MK;Ghosh A;Tripathi R;Sinha PR;Sharma A;Hesemann NP;Chaurasia SS;Giuliano EA;Mohan RR
通讯作者：
Mohan RR
影响因子：
1.6
作者：
Donnelly, Kevin S.;Giuliano, Elizabeth A.;Mohan, Rajiv R.
通讯作者：
Mohan, Rajiv R.
影响因子：
--
作者：
FANTES, FE;HANNA, KD;SAVOLDELLI, M
通讯作者：
SAVOLDELLI, M
影响因子：
1.6
作者：
Donnelly, Kevin S.;Giuliano, Elizabeth A.;Mohan, Rajiv R.
通讯作者：
Mohan, Rajiv R.
影响因子：
1.6
作者：
Gronkiewicz KM;Giuliano EA;Sharma A;Mohan RR
通讯作者：
Mohan RR