Obesity and Allergic Airway Hyperresponsiveness

University Of Texas Hlth Sci Ctr Houston, Houston TX

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Abstract

DESCRIPTION (provided by applicant): Obesity increases the risk of incident asthma. However, the mechanistic basis for this relationship is poorly understood. Our published data demonstrate that obese as compared to lean, wild-type mice exhibit increased airway responsiveness to methacholine but decreased numbers of bronchoalveolar lavage fluid eosinophils. Recent data from humans demonstrate that obesity does not promote the development of airway hyperresponsiveness (AHR) in obese asthmatics by enhancing airway inflammation, but rather, by enhancing chronic systemic inflammation, which is characterized by increased serum concentrations of hormones, cytokines, chemokines, and soluble cytokine receptors. These substances, collectively termed adipokines, are largely pro-inflammatory in nature. Of the adipokines increased in obesity, our preliminary data implicate resistin, a hormone and a pro-inflammatory cytokine, as a key mediator for the development of obesity- induced, chronic systemic inflammation, and potentially, AHR in obese asthmatics. Consequently, the major goal of this proposal is to investigate resistin, as the causative link, at the molecular level, by which obesity increases the risk of incident asthma. We and others have demonstrated that resistin mediates the expression of several inflammatory moieties elevated in obesity-induced, chronic systemic inflammation. Importantly, these same inflammatory moieties can elicit allergic AHR. Recently, we discovered an isoform of decorin (¿DCN) as a receptor for resistin that is expressed on adipose stromal cells (ASC) from white adipose tissue (WAT). ASC are known to exert context-dependent immunomodulatory effects, which have not been well- studied in asthma. Because ASC exhibit a pro-inflammatory phenotype in obesity, we hypothesize that resistin-activated ASC cooperate in establishing and sustaining AHR in obese asthmatics by augmenting the development of chronic systemic inflammation in these individuals. Based on these observations, we propose to test the central hypothesis that obesity-induced increases in resistin promote the development of AHR in asthma through the augmentation of chronic systemic inflammation via resistin-¿DCN signaling in ASC from WAT. We propose two Specific Aims to test this hypothesis. In Aim 1, we shall examine the contribution of resistin to the development of chronic systemic inflammation and increases in airway responsiveness to methacholine in obese mice genetically deficient in resistin. In Aim 2, we shall determine the ability of 3T3-L1 ASC, engineered to over-express ¿DCN, to synthesize and/or release adipokines in response to resistin. These investigations will illuminate the role of resistin-¿DCN signaling in the development of obesity-induced, chronic systemic inflammation, and potentially, AHR, in obese asthmatics. These outcomes will be useful for developing preventative or palliative therapies directed at interfering with resistin's detrimental effects on pulmonary biology in the obese.