Norepinephrine Attenuates Benzalkonium Chloride-Induced Dry Eye Disease by Regulating the PINK1/Parkin Mitophagy Pathway.

IF 2.6 4区 医学 Q2 OPHTHALMOLOGY Ocular Immunology and Inflammation Pub Date : 2024-12-27 DOI:10.1080/09273948.2024.2447816
Han Zhao, Wushuang Wang, Yun Yang, Changming Feng, Tong Lin, Lan Gong
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Abstract

Background: Increased reactive oxygen species (ROS) are involved in the pathological process of dry eye disease. Our previous results suggested that norepinephrine (NE) has a protective effect on dry eye.

Purpose: This study explored the potential therapeutic role and underlying mechanisms of NE in benzalkonium chloride (BAC)-induced dry eye disease.

Methods: BAC-pretreated human corneal epithelial cells (HCEpiC) were cultured with various concentrations of NE. A BAC-induced dry eye mice model was established to explore the role of NE. Alterations in mice corneal tissues, ROS levels, mitochondrial function, and mitophagy levels were analyzed.

Results: In vitro, our results revealed that BAC-exposed HCEpiC led to mitochondrial malfunction, which involved excessive ROS production, decreased mitochondrial membrane potential (MMP), and promoted mitochondrial fragmentation through increased DRP1 and fission protein 1 (Fis1) expression and reduced mitofusin 2 (Mfn2) expression. Moreover, topical BAC application induced excessive mitophagy. These effects were reversed by NE. Additionally, the increased expression of LC3B, SQSTM1/p62, PINK1, and Parkin, which control mitophagy, in BAC-exposed HCEpiC was suppressed by NE. In BAC-induced C57BL/6J mice, NE resulted in lower fluorescein staining scores, decreased TUNEL-positive cells, and decreased mitochondrial fragmentation.

Conclusions: In conclusion, our findings showed that NE therapy prevented HCEpiC following BAC application by regulating mitochondrial quality control, which is controlled by PINK1/Parkin-dependent mitophagy. Our research suggests a potential targeted treatment for dry eye disease.

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去甲肾上腺素通过调节PINK1/Parkin线粒体自噬途径减轻苯扎氯铵诱导的干眼病。
背景:活性氧(ROS)的增加参与了干眼病的病理过程。我们之前的研究结果表明,去甲肾上腺素(NE)对干眼症有保护作用。目的:探讨NE在苯扎氯铵(benzalkonium chloride, BAC)诱发的干眼病中的潜在治疗作用及其机制。方法:用不同浓度的NE培养bac预处理的人角膜上皮细胞(HCEpiC)。建立bac诱导小鼠干眼模型,探讨NE的作用。分析小鼠角膜组织、ROS水平、线粒体功能和线粒体自噬水平的变化。结果:在体外,我们的研究结果显示,bac暴露的HCEpiC导致线粒体功能障碍,包括过量的ROS产生,降低线粒体膜电位(MMP),并通过增加DRP1和裂变蛋白1 (Fis1)表达和降低mitofusin 2 (Mfn2)表达促进线粒体断裂。此外,局部应用BAC诱导了过度的线粒体自噬。这些影响被NE逆转了。此外,在bac暴露的HCEpiC中,控制有丝分裂的LC3B、SQSTM1/p62、PINK1和Parkin的表达增加被NE抑制。在bac诱导的C57BL/6J小鼠中,NE导致荧光素染色评分降低,tunel阳性细胞减少,线粒体断裂减少。结论:总之,我们的研究结果表明,NE治疗通过调节线粒体质量控制来预防BAC后的HCEpiC,线粒体质量控制由PINK1/帕金森依赖性线粒体自噬控制。我们的研究为干眼症提供了一种潜在的靶向治疗方法。
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来源期刊
CiteScore
6.20
自引率
15.20%
发文量
285
审稿时长
6-12 weeks
期刊介绍: Ocular Immunology & Inflammation ranks 18 out of 59 in the Ophthalmology Category.Ocular Immunology and Inflammation is a peer-reviewed, scientific publication that welcomes the submission of original, previously unpublished manuscripts directed to ophthalmologists and vision scientists. Published bimonthly, the journal provides an international medium for basic and clinical research reports on the ocular inflammatory response and its control by the immune system. The journal publishes original research papers, case reports, reviews, letters to the editor, meeting abstracts, and invited editorials.
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