Zhu Shuyan, Shan Huimin, Li Jianqiao, Pan Lijie, Wang Shudan, Zhu Jing, Guo Hui, Mi Fenghua, Wu Xinyi, Yin Jia, Pang Kunpeng
Xi'an People's Hospital (Xi'an Fourth Hospital), Shanxi Eye Hospital, Xi'an, Shanxi, China.
Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Front Pharmacol. 2022 Oct 21;13:996635. doi: 10.3389/fphar.2022.996635. eCollection 2022.
Transdifferentiation of keratocytes into fibroblasts or further into myofibroblasts, which produced denser and more disorganized extracellular matrix, is the major cause of corneal fibrosis and scarring, leading to corneal blindness. TGF-β1 is the critical cytokine for the myofibroblast's transdifferentiation and survival. Hypoxia Inducible Factor (HIF) was found to play an important role in promoting fibrosis in lung, kidney, and dermal tissues recently. Our preliminary study demonstrated that topical administration of the acriflavine (ACF), a drug inhibiting HIF dimerization, delayed corneal opacity and neovascularization after the alkali burn. To know whether ACF could prevent corneal fibrosis and improve corneal transparency, we created a mouse mechanical corneal injury model and found that topical administration of ACF significantly inhibited corneal fibrosis at day 14 post-injury. The reduction of myofibroblast marker α-SMA, and fibronectin, one of the disorganized extracellular matrix molecules, in the corneal stroma were confirmed by the examination of immunohistochemistry and real-time PCR. Furthermore, the ACF inhibited the expression of α-SMA and fibronectin in both TGF-β1 stimulated or unstimulated fibroblasts . This effect was based on the inhibition of HIF signal pathways since the levels of the HIF-1α downstream genes including Slc2a1, Bnip3 and VEGFA were downregulated. To our knowledge, this is the first time to implicate that HIFs might be a new treatment target for controlling corneal fibrosis in mechanical corneal injuries.
角膜细胞向成纤维细胞进而向肌成纤维细胞的转分化会产生更致密且更无序的细胞外基质，这是角膜纤维化和瘢痕形成的主要原因，可导致角膜盲。转化生长因子-β1（TGF-β1）是肌成纤维细胞转分化和存活的关键细胞因子。最近发现缺氧诱导因子（HIF）在促进肺、肾和皮肤组织纤维化中起重要作用。我们的初步研究表明，局部应用吖啶黄（ACF），一种抑制HIF二聚化的药物，可延缓碱烧伤后的角膜混浊和新生血管形成。为了解ACF是否能预防角膜纤维化并改善角膜透明度，我们建立了小鼠机械性角膜损伤模型，发现局部应用ACF在损伤后第14天可显著抑制角膜纤维化。通过免疫组织化学和实时PCR检测证实，角膜基质中肌成纤维细胞标志物α-平滑肌肌动蛋白（α-SMA）和纤连蛋白（一种无序的细胞外基质分子）减少。此外，ACF抑制TGF-β1刺激或未刺激的成纤维细胞中α-SMA和纤连蛋白的表达。这种作用基于对HIF信号通路的抑制，因为包括Slc2a1、Bnip3和VEGFA在内的HIF-1α下游基因的水平下调。据我们所知，这是首次表明HIF可能是控制机械性角膜损伤中角膜纤维化的新治疗靶点。
