The majority of severe asthmatics in the U.S. are obese, and obesity is a major risk factor for asthma. Both chronic inflammation associated with asthma and metabolic alterations associated with obesity results in increased oxidative stress and altered redox homeostasis, which likely contributes to disease pathology. Our recent studies identified the NADPH oxidase DUOX1, a major enzymatic source of reactive oxygen species (ROS) within the respiratory epithelium, as a mediator of innate type 2 inflammatory responses to allergens and of clinically relevant features of allergic airway disease in a mouse model of allergic asthma. Preliminary studies of human obese allergic asthmatics or mice with diet-induced obesity (DIO) further indicate that obesity is associated with enhanced production of type 2 cytokines (IL-33, IL-13) in response to allergen challenge. Moreover, preliminary data indicate close and reciprocal interactions between airway epithelial DUOX1 and mitochondrial ROS production, which is associated with enhanced redox-mediated activation and mitochondrial translocation of the tyrosine kinases Src and epidermal growth factor receptor (EGFR), and suggests that enhanced DUOX1 activation in combination with altered mitochondrial integrity and function results in worsened redox perturbations in obese asthma.
The Specific Aims of this proposal are 1) to determine the effect of obesity on airway DUOX1 expression and activation and its role in innate cytokine responses to allergen challenge; 2) to assess the interactions between DUOX1 and mitochondrial ROS production, ATP production or glycolysis, and the role of mitochondrial targeting of EGFR/Src pathways; and 3) to evaluate the functional importance of DUOX1-mitochondrial interactions in obese allergic airways disease. Collectively, these studies will address how enhanced DUOX1 in combination with mitochondrial dysfunction due to obesity contributes to epithelial redox perturbations and altered epithelial allergen responses, as a critical mechanism of enhanced or immune responses and airway remodeling in obesity-related asthma.

Public Health Relevance

The majority of severe asthmatics in the U.S. are obese, and obese asthmatics often respond poorly to standard therapy. Allergic inflammation and metabolic alterations due to obesity are associated with oxidative stress, yet the contribution(s) of oxidative mechanisms to disease pathology are not well understood. This project will address the importance of the NADPH oxidase DUOX1, a major oxidant source within the respiratory epithelium, combined with mitochondrial dysfunction, as an important feature of metabolic disease in mediating redox- dependent processes leading to altered or exaggerated allergic inflammation due to obesity.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Noel, Patricia
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University of Vermont & St Agric College
Schools of Medicine
United States
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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
Heppner, David E; Hristova, Milena; Ida, Tomoaki et al. (2018) Cysteine perthiosulfenic acid (Cys-SSOH): A novel intermediate in thiol-based redox signaling? Redox Biol 14:379-385
Heppner, David E; Dustin, Christopher M; Liao, Chenyi et al. (2018) Direct cysteine sulfenylation drives activation of the Src kinase. Nat Commun 9:4522
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
van der Vliet, Albert; Danyal, Karamatullah; Heppner, David E (2018) Dual oxidase: a novel therapeutic target in allergic disease. Br J Pharmacol 175:1401-1418
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