S-glutathionylation chemistry in fibrotic lung remodeling

纤维化肺重塑中的 S-谷胱甘肽化学

• 批准号: 10585922
• 负责人: Yvonne M. W. Janssen-Heininger
• 金额: $ 92.76万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10585922
• 关键词: Address; Animals; Antioxidants; Area; Asthma; Attenuated; Biological; Biological Process; Cells; Chemicals; Chemistry; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Client; Clinical; Clinical Trials; Complex; Cysteine; Data; Disease model; Enzymes; Epithelial Cells; Fibrosis; Foundations; Functional disorder; Glutathione; Glutathione S-Transferase P; Goals; Grx1 protein; Immune response; Inflammatory; Knowledge; Laboratories; Lung; Lung diseases; Modification; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Patients; Pharmaceutical Preparations; Play; Process; Protein S; Proteins; Pulmonary Fibrosis; Research; Role; Signal Transduction; Structure of parenchyma of lung; Therapeutic; Thinking; Translations; Work; airway remodeling; allergic airway disease; antioxidant therapy; asthmatic; attenuation; clinical practice; combat; fibrotic lung; improved; interstitial; mouse model; novel therapeutics; oxidation; penicillamine-glutathione mixed disulfide; peroxiredoxin; programs; protein function; pulmonary function; response; scaffold; success; uptake

PROJECT SUMMARY It is increasingly recognized that oxidative stress is an important feature in pathophysiology of chronic pulmonary diseases, including asthma, COPD and pulmonary fibrosis. Yet, in spite of some successes in animal studies, clinical trials using antioxidants have been largely ineffective in improving lung function in patients with lung disease, and have not yielded new drugs. Despite these negative clinical trials, it has now become well accepted that oxidants are molecules that carry out important biological functions. My laboratory has discovered that protein S-glutathionylation (PSSG), a redox-based modification of reactive cysteines, plays a critical role in airways remodeling and lung fibrosis. We identified that this process is catalyzed by glutathione S transferase P (GSTP), and reversed by the deglutathionylating enzyme, glutaredoxin-1 (Glrx1) induced de-glutathionylation. The intriguing observations around the GSTP-PSSG-Glrx1 redox axis have formed the foundation for a number of research directions that will be pursued herein. We propose to do so in the setting of interstitial fibrosis and fibrotic remodeling associated with allergic airways disease. The conceptual framework for this R35 over the next seven years consists of five separate goals that include: 1) Identification of redox scaffolds and redox-relay circuits harnessed by scaffolding complexes that encompass peroxiredoxin-4 (Prdx4), GSTP and client proteins that are S-glutathionylated via a redox relay, 2) Avenues to combat protein S-glutathionylation (PSSG) in a target-specific manner by focusing on new avenues for inhibition of GSTP, 3) Understanding mechanisms of cellular uptake/secretion of Glrx1, approaches to modify stability of and deliver Glrx1 to specific cellular compartments to enhance its de-glutathionylating function, 4) Address whether altered inflammatory/immune responses contribute to the diminished fibrogenic response upon attenuation of S-glutathionylation, and 5) Elucidate targets for PSSG in epithelial cells from asthmatics and lung tissues from patients with IPF and address whether strategies to attenuate PSSG diminish pro-inflammatory/pro-remodeling responses in epithelial cells from patients with asthma: The project areas identified have the strong potential to advance our knowledge of how biological oxidations, specifically PSSG, are controlled, with the goal to identify strategies to intervene with protein cysteine oxidations in a target- or compartment-specific manner. The anticipated outcomes will be molecules that are therapeutically applicable and overcome the lack of efficacy observed with the use of non- specific generic antioxidants in the treatment of pulmonary diseases. This research program has the potential to be paradigm-shifting as it changes conventional thinking of how oxidants contribute to lung disease (oxidative stress) toward a paradigm wherein oxidants transduce signals via highly scaffolded “electrical circuits”.

项目摘要 人们越来越认识到氧化应激是慢性肺疾病病理生理学的重要特征 这些疾病包括哮喘、COPD和肺纤维化。然而，尽管在动物研究中取得了一些成功， 使用抗氧化剂的临床试验在改善肺结核患者的肺功能方面基本无效， 但是，它没有产生新的药物。尽管有这些负面的临床试验，但它现在已经被广泛接受。 氧化剂是执行重要生物功能的分子。我的实验室发现 蛋白S-谷胱甘肽化（PSSG）是一种基于氧化还原的反应性半胱氨酸修饰， 气道重塑和肺纤维化。我们发现这个过程是由谷胱甘肽S转移酶P催化的， （GSTP），并逆转脱谷胱甘肽化酶，谷氧还蛋白-1（Glrx 1）诱导脱谷胱甘肽化。 围绕GSTP-PSSG-Glrx 1氧化还原轴的有趣观察形成了一些基础， 的研究方向，将在此进行。我们建议在间质纤维化的情况下这样做， 与过敏性气道疾病相关的纤维化重塑。R35的概念框架， 未来七年包括五个独立的目标，包括：1）确定氧化还原支架和氧化还原中继 由包含过氧化物氧还蛋白-4（Prdx 4）、GSTP和客户蛋白的支架复合物控制的回路 通过氧化还原中继被S-谷胱甘肽化，2）在蛋白质中对抗S-谷胱甘肽化（PSSG）的途径， 3）了解全球贸易优惠制的机制， Glrx 1的细胞摄取/分泌，改变Glrx 1的稳定性并将Glrx 1递送至特定细胞的方法， 4）解决是否改变了炎症/免疫功能， 响应有助于在S-谷胱甘肽化减弱后减少的纤维化响应，和5） 阐明PSSG在哮喘患者上皮细胞和IPF患者肺组织中的靶点， 减弱PSSG的策略是否减少了上皮细胞中的促炎/促重塑反应 从哮喘患者：确定的项目领域有很大的潜力，以提高我们的知识， 如何控制生物氧化，特别是PSSG，目的是确定干预策略， 蛋白质半胱氨酸以靶或区室特异性方式氧化。预期的结果将是 治疗上适用的分子，并克服了使用非- 治疗肺部疾病的特定通用抗氧化剂。这项研究计划有可能 是范式转变，因为它改变了传统的思维如何氧化剂有助于肺部疾病（氧化 应力）向其中氧化剂通过高度支架化的“电路”阻断信号的范例发展。

项目成果

Downregulation of DUOX1 function contributes to aging-related impairment of innate airway injury responses and accelerated senile emphysema.

• DOI: 10.1152/ajplung.00021.2021
• 发表时间: 2021-05
• 期刊: American journal of physiology. Lung cellular and molecular physiology
• 作者: C. Schiffers;L. Lundblad;Milena Hristova;A. Habibovic;Christopher M. Dustin;N. Daphtary;M. Aliyeva;D. Seward;Y. Janssen-Heininger;E. Wouters;N. Reynaert;A. Vliet

Glutathione S-transferases and their implications in the lung diseases asthma and chronic obstructive pulmonary disease: Early life susceptibility?

• DOI: 10.1016/j.redox.2021.101995
• 发表时间: 2021-07
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: van de Wetering C;Elko E;Berg M;Schiffers CHJ;Stylianidis V;van den Berge M;Nawijn MC;Wouters EFM;Janssen-Heininger YMW;Reynaert NL
• 通讯作者: Reynaert NL

Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome.

• DOI: 10.1016/j.redox.2017.04.020
• 发表时间: 2017-08
• 期刊: Redox biology
• 影响因子: 11.4
• 作者: Hoyt LR;Randall MJ;Ather JL;DePuccio DP;Landry CC;Qian X;Janssen-Heininger YM;van der Vliet A;Dixon AE;Amiel E;Poynter ME
• 通讯作者: Poynter ME

S-Glutathionylation-Controlled Apoptosis of Lung Epithelial Cells; Potential Implications for Lung Fibrosis.

• DOI: 10.3390/antiox11091789
• 发表时间: 2022-09-10
• 期刊: ANTIOXIDANTS
• 影响因子: 7
• 作者: Corteselli, Elizabeth;Aboushousha, Reem;Janssen-Heininger, Yvonne
• 通讯作者: Janssen-Heininger, Yvonne