Obese asthma represents an important clinical problem due to the growing number of affected patients worldwide, and their disease severity which is poorly controlled with existing medications. Changes in metabolism, and associated changes in redox homeostasis are believed to contribute to obesity-associated diseases. This project addresses whether S-glutathionylation chemistry (PSSG, a redox-based modification of protein cysteine residues involving conjugation with glutathione) contributes to the pathogenesis of obese allergic asthma. We have discovered a close association between PSSG chemistry and glycolysis in lungs from mice with house dust mite (HDM)-induced allergic airways disease, and in primary nasal epithelial cells from asthmatics. Redox proteomics identified he glycolytic enzyme, pyruvate kinase M2 (PKM2) as an important target for S-glutathionylation. PKM2 had recently been implicated in the augmentation of pro-inflammatory responses. Importantly, both PSSG and glycolysis were increased in settings of obesity, suggesting that PSSG and linked alterations in glycolysis may be a key feature of obese allergic asthma. These findings led us to hypothesize that glycolysis is a critical process that promotes allergic airways disease, and that this process is enhanced by S-glutathionylation of the glycolytic enzyme PKM2 (PKM2-SSG). We furthermore hypothesize that these processes are augmented in obese asthmatic individuals compared to lean allergic asthmatics. Avenues to inhibit glutathione S-transferase P (GSTP, a catalyst of S-glutathionylation) or to promote de-glutathionylation of PKM2 by increasing expression of the de-glutathionylating enzyme, glutaredoxin-1 (GLRX), are anticipated to attenuate glycolytic reprogramming and to decrease airways disease in obese allergic asthmatics.
In Specific Aim #1 we will determine the impact of genetic ablation or inhibition of GSTP in decreasing glycolysis in mice house dust mite (HDM)- diet induced obesity (DIO)- mediated lung disease, and in nasal epithelial cells from lean and obese allergic asthmatics.
In Specific Aim #2 we propose to assess the impact of modulation of GLRX in lung tissues in order to attenuate PSSG, PKM2-SSG, and glycolysis in settings of lean or obese allergic airways disease. We will utilize transgenic approaches or administer recombinant GLRX directly into airways of lean or obese mice with existing allergic airways disease.
Specific Aim #3 addresses the importance of pyruvate kinase M2 for lean or obese allergic airways disease. We will specifically ablate the Pkm2 gene from airway epithelial cells in mice and propose pharmacological approaches to enhance PKM2 activity in mice with existing HDM/DIO-induced allergic disease and in nasal epithelial cells derived from lean or obese healthy subjects or asthmatics. Completion of the proposed studies will provide new mechanistic insights into how S- glutathionylation facilitates glycolytic reprogramming and has the potential to offer clinically/translationally relevant strategies targeting S-glutathionylation chemistry in order to attenuate glycolysis, resultant lactate production, airways inflammation and remodeling in individuals with obese allergic asthma.
Obesity is a risk factor for the development of asthma, and obese asthmatics tend to have severe and poorly controlled disease. The underlying factors that contribute to increased disease severity in obese asthmatics are currently largely unknown. This proposal addresses whether changes in oxidant status are an important factor in obese asthma and whether oxidant-induced changes in glucose metabolism (Glycolysis) contribute to disease severity in obese asthmatics.
| 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 |
| Peters, Ubong; Dixon, Anne E; Forno, Erick (2018) Obesity and asthma. J Allergy Clin Immunol 141:1169-1179 |
| Peters, Ubong; Suratt, Benjamin T; Bates, Jason H T et al. (2018) Beyond BMI: Obesity and Lung Disease. Chest 153:702-709 |
| 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 |
