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?.
Oxidants are molecule that are known to be important to remodeling of lung tissue in patients with asthma and pulmonary fibrosis. However so far antioxidant therapies have failed. We believe that this is due to the non- specific action of generic antioxidants. My laboratory has discovered that oxidants can change the function of proteins, chemical messengers in cells of the lung, by adding a glutathione molecule to these proteins, a process known as protein S-glutathionylation. The goal of this proposal is to understand the importance of the process of S-glutathionylation in patients with asthma or pulmonary fibrosis, and in mouse models of these diseases. The goal is to understand how this process of S-glutathionylation works, and whether the enzymes that regulate this process can be a target for more specific drugs. We believe that these questions are important for translation into clinical practice as we already have data with compounds that can be used clinically.
|Qian, Xi; Aboushousha, Reem; van de Wetering, Cheryl et al. (2018) IL-1/inhibitory ?B kinase ?-induced glycolysis augment epithelial effector function and promote allergic airways disease. J Allergy Clin Immunol 142:435-450.e10|
|Anathy, Vikas; Lahue, Karolyn G; Chapman, David G et al. (2018) Reducing protein oxidation reverses lung fibrosis. Nat Med 24:1128-1135|
|Zhang, Jie; Ye, Zhi-Wei; Chen, Wei et al. (2018) S-Glutathionylation of estrogen receptor ? affects dendritic cell function. J Biol Chem 293:4366-4380|
|van der Velden, Jos L; Wagner, Darcy E; Lahue, Karolyn G et al. (2018) TGF-?1-induced deposition of provisional extracellular matrix by tracheal basal cells promotes epithelial-to-mesenchymal transition in a c-Jun NH2-terminal kinase-1-dependent manner. Am J Physiol Lung Cell Mol Physiol 314:L984-L997|
|van der Vliet, Albert; Janssen-Heininger, Yvonne M W; Anathy, Vikas (2018) Oxidative stress in chronic lung disease: From mitochondrial dysfunction to dysregulated redox signaling. Mol Aspects Med 63:59-69|
|Chapman, D G; Mougey, E B; Van der Velden, J L et al. (2017) The Duffy antigen receptor for chemokines regulates asthma pathophysiology. Clin Exp Allergy 47:1214-1222|
|Eurlings, Irene M J; Reynaert, Niki L; van de Wetering, Cheryl et al. (2017) Involvement of c-Jun N-Terminal Kinase in TNF-?-Driven Remodeling. Am J Respir Cell Mol Biol 56:393-401|
|Hoyt, Laura R; Randall, Matthew J; Ather, Jennifer L et al. (2017) Mitochondrial ROS induced by chronic ethanol exposure promote hyper-activation of the NLRP3 inflammasome. Redox Biol 12:883-896|
|Heppner, David E; Janssen-Heininger, Yvonne M W; van der Vliet, Albert (2017) The role of sulfenic acids in cellular redox signaling: Reconciling chemical kinetics and molecular detection strategies. Arch Biochem Biophys 616:40-46|
|Pociask, Derek A; Robinson, Keven M; Chen, Kong et al. (2017) Epigenetic and Transcriptomic Regulation of Lung Repair during Recovery from Influenza Infection. Am J Pathol 187:851-863|