Asthma is more prevalent in adult females than males. In addition, nearly 40% of patients with asthma in the US are obese. Adult female obese asthma patients experience increased asthma severity with diminished responsiveness to standard medications compared to male and lean asthma patients. Obesity is associated with inflammatory and metabolic changes that contribute to asthma pathobiology. Specifically, systemic metabolic changes in the obese patient, including increased levels of leptin, a pro-inflammatory mediator secreted by adipose tissue, augments pathogenic processes in asthma by acting directly on structural cells in the airway. Airway remodeling describes airway structural changes in asthma, including airway fibrosis, that can result in permanent airway obstruction. The mechanisms directing airway remodeling in female obese asthma are particularly poorly understood. Our preliminary data show that airway fibrosis is significantly elevated in obese female patients with allergic asthma compared to male obese allergic asthma patients. Furthermore, leptin augments chronic allergen-induced airway fibrosis, small airways resistance and eosinophilic inflammation in female mice compared to male mice. Our overarching hypothesis is that, in obese asthma, males are protected from the combined effects of chronic leptin and allergen exposure on airway pathology compared to females. We further hypothesize that adipose tissue in obese female allergic asthmatics secretes increased leptin and pro-fibrotic growth factors than their male counterparts and that these changes contribute to airway inflammation and fibrosis in allergic asthma through a mechanism requiring PPARg inhibition. We will test this hypothesis by confirming the contribution of biological sex to pathologic airway and adipose responses in a mouse model of chronic obesity and allergic airways disease (Aim 1), and by testing the sex-specific influence of visceral adipose tissue-derived secreted factors on airway fibroblast cellular responses and lung function in human obese asthma (Aim 2). The studies described in this proposal will extend the studies proposed in our original R01 to specifically address sex-specific differences in obese asthma and they will address two objectives listed in the strategic goals of the 2019-2023 Trans-NIH Strategic Plan for Women?s Health Research: to discover basic biological differences between females and males and investigate the influence of sex and gender on disease prevention, presentation, management and outcomes. Successful completion of these Aims will increase our understanding of the unique cellular and metabolic mechanisms directing the pathobiology of female obese asthma.
The combined factors of obesity and female sex significantly escalate the risk of development of asthma and increase asthma severity in adult patients. The overall goal of this proposed research is to further investigate the specific effect of sex differences on mechanisms whereby hormones involved in obesity interact with immune responses in allergic asthma to promote pathologic adipose tissue and airway structural changes. By increasing our knowledge of the effects that obesity has on cellular functions and signaling interactions between adipose tissue and the airway, we hope to identify novel uses for current therapies or to discover potential therapeutic targets for treatment of obese asthma.
