Allergic asthma, a disease that affects over 300 million people worldwide, is typically driven by Th2-dominated immune responses to environmental antigens. Obesity, a disorder afflicting 500 million people worldwide, is associated with chronic inflammation, elevated proinflammatory cytokine production, and metabolic dysfunction leading to the development of diabetes, cardiovascular disease, non-alcoholic fatty liver disease and various cancers. Recent evidence suggests the existence of several asthma ?endotypes?? disease subtypes driven by unique underlying pathogenic mechanisms. The ?obese asthma? endotype is associated with: (1) a shift away from Th2-dominated inflammation towards a more proinflammatory phenotype; (2) a reduction in therapeutic efficacy of steroids; and (3) a clear female bias in prevalence. While there is consensus regarding these clinical parameters, identification of underlying mechanisms of ?obese asthma? has been hampered by the absence of a combined model of severe obesity and asthma in female mice. Although reproducible modeling of asthma is achieved in both male and female mice, modeling of obesity and metabolic dysfunction is largely limited to male mice. This is largely in part due to poor tractability of obesity and metabolic dysfunction in female mice. Our novel data demonstrate that housing female mice in temperatures close to their thermoneutral zone (the temperature at which they are in metabolic homeostasis ? 30-33C) with concomitant HFD feeding promotes development of severe obesity, adiposity and metabolic dysfunction comparable to that observed in male mice. Thus, we are now able to simultaneously assess the influence of obesity, adiposity, metabolic dysfunction, and sex on asthma pathogenesis. In this application, our two independent, yet related, Specific Aims seek to validate the ability of our novel model to recapitulate three frequent observations in obese asthmatics: (1) the shift towards a proinflammatory profile; (2) reduced efficacy of steroids; and (3) female preponderance.
Specific Aim 1 : Determine if severely obese female mice with metabolic dysfunction develop asthma comparable to the ?obese asthma? endotype described in obese women. Using HFD- or control chow diet-fed male and female mice, housed at either standard (22C) or thermoneutral (30-33C) conditions, we will induce experimental asthma in a model of robust obesity and metabolic dysfunction. Features of experimental asthma will be correlated with weight gain, adiposity, parameters of metabolic dysfunction, in a sex-dependent manner.
Specific Aim 2 : Determine if obesity and metabolic dysfunction associate with development of steroid refractory asthma in female mice. The ability of inhaled and systemic steroids to inhibit experimental asthma and metabolic dysfunction will be assessed in HDM-challenged, HFD- or control diet-fed, TS- and TN- housed male and female mice. A better understanding of the pathogenesis of the ?obese asthma? endotype will revolutionize care of obese asthmatics and allow for discovery of novel therapeutic approaches benefiting a large proportion of those underserved by current therapeutic modalities.
Allergic asthma, a chronic inflammatory lung disease, afflicts more than 300 million people worldwide. In parallel, the obesity pandemic affecting over 500 million people worldwide continues unabated. Clinical evidence demonstrates a unique ?obese asthma? endotype that disproportionately affects women, and is associated with poor response to common therapeutics. This application aims to utilize a completely new experimental model of obesity in female mice to examine the interplay among obesity and gender on the ?obese asthma? endotype and therapeutic responsiveness. Defining how obesity modulates asthma development in female mice would uncover novel therapeutic targets for treatment of asthma in the majority of individuals underserved by current therapeutics.
