The majority of severe asthmatics in the U.S. are obese, and among obese asthmatics, those with early-onset allergic (EOA) disease suffer with particularly severe disease. Relationships between metabolic, immunologic, and physiologic alterations, and how they are affected by weight loss, remain poorly understood in EOA obese asthma. Especially striking is a gap in knowledge of how adipose-derived mediators affect the lung to cause alterations in airway epithelial mitochondrial function that augment baseline and allergen-induced cytokine production to cause the structural and physiologic lung alterations characteristic of obese allergic asthma. We hypothesize that circulating factors from visceral adipose tissue of early onset allergic (EOA) obese asthmatics cause mitochondrial dysfunction in airway epithelial cells that increases sensitivity to allergenic triggers, and the release of soluble factors that amplify EOA asthma in obesity, events that are reversed by weight loss. We will address this hypothesis through a combination of studies using materials collected from subjects enrolled in a longitudinal study of (EOA) asthmatics undergoing bariatric surgery, as well as by using novel mouse models.
In Specific Aim #1, we will determine the effects of weight loss on the response to in vivo allergen challenge in obese allergic asthmatic patients and how this relates to changes in mitochondrial reactive oxygen species and calcium handling affecting cytokine response to allergen in airway epithelial cells.
In Specific Aim #2, we will determine which circulating mediators elevated in obese asthmatics, as well as factors produced from visceral adipose tissue, induce cytokine secretion from airway epithelium. We will quantitate specific proteins in the plasma and made by adipose tissue, then culture human bronchiolar epithelial (HBE) cells and nasal epithelial cells with plasma or adipose tissue-conditioned media in the absence and presence of HDM extract to identify secreted epithelial-derived cytokines. We will also analyze primary nasal epithelial cells from normal weight and obese asthmatics prior to and following bariatric surgery to determine differences in cytokine expression and production. Finally, we will neutralize airway epithelial- activating mediators in the plasma to determine the impact on secretion of epithelial factors.
In Specific Aim #3, we will determine the consequences of adipose-activated airway epithelial cells on features of asthma using novel mouse models of diet-induced obesity and surgical or dietary weight loss, as well as the in vivo neutralization of adipose- and epithelial-derived factors, to examine the impact on allergic asthma associated with obesity. Airway epithelial cells will be assessed for alterations in mitochondrial metabolism and the impact of mediator inhibition on lung structure and methacholine responsiveness will be assessed. These clinical and preclinical studies will provide a better understanding of how altered airway cellular function is affected by obesity and impacts upon the pathogenesis of obesity-associated asthma, the mechanisms by which weight loss elicits clinical benefit, and will test the efficacy of potential biological therapeutics in valuable preclinical disease models.
Patients with allergic asthma that are obese suffer with much more severe disease than patients who are not obese, and current therapies do not work as well in obese as in lean patients. Our objective is to explore the contribution of the specific cells and their secreted mediators that are released from visceral adipose tissue of obese allergic asthmatics to the mitochondrial function of airway epithelial cells and their activation by allergen, which then cause the structural alterations and methacholine hyperresponsiveness that manifest in severe disease in obese allergic asthmatics. The ultimate purpose of this work is to understand why allergic asthma is so much more severe in patients with obesity, and to develop therapies specifically targeted for such patients.
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