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”.

项目成果

The Flow-Volume Loop: Always an Inspiration!

• DOI: 10.1080/15412555.2020.1758050
• 发表时间: 2020-06-05
• 期刊: COPD-JOURNAL OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE
• 影响因子: 2.2
• 作者: Irvin, Charles G.

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

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

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

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