Obesity, Inflammation and Response to Therapy in Asthma

Summary

Principal Investigator: EVERETT SUTHERLAND
Abstract: Emerging evidence suggests a relationship between obesity and asthma, although the precise nature of this relationship is not known. While obesity may increase airway inflammation or physiologic impairment, thereby elevating the risk of incident asthma or causing a more severe asthma phenotype, it is also possible that the effects of obesity on individuals with asthma are exerted not by alterations in airway inflammation per se, but rather by associated systemic inflammatory processes which attenuate the response to controller therapies such as inhaled corticosteroids. On the basis of preliminary studies demonstrating evidence of glucocorticoid (GC) insensitivity and systemic inflammation in overweight and obese asthmatics, we postulate that the systemic inflammatory state associated with obesity may have important biological effects on prognosis and response to therapy in asthma, in part by mediating the development of GC insensitivity. We propose to test the following interrelated hypotheses in a time-sensitive ancillary study complementing 2 upcoming clinical trials of the Asthma Clinical Research Network: Hypothesis 1: Overweight/obese asthmatics are more likely than asthmatics of normal weight ("lean asthmatics") to manifest GC insensitivity. Associated specific aims will determine: 1) immunologic response to GCs of peripheral blood mononuclear cells (PBMC) from overweight/obese vs. lean asthmatics, 2) expression of biomarkers of GC insensitivity in induced sputum cells from these groups and 3) if biomarkers of GC insensitivity are predictive of attenuated response to inhaled corticosteroid (ICS) therapy. Hypothesis 2: Overweight/obese asthmatics are more likely than lean asthmatics to demonstrate systemic inflammation, resulting in increased expression of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-?) and other proinflammatory cytokines and leading to GC insensitivity. Associated specific aims will determine: 1) if cytokines and other biomarkers of systemic inflammation (IL-6, TNF-?, leptin, CRP) are increased in overweight/obese vs. lean asthmatics, 2) if cytokines and other biomarkers of systemic inflammation found to be elevated in overweight/obese asthmatics reduce GC sensitivity of PBMCs from GC- sensitive asthmatics and 3) determine if biomarkers of systemic inflammation are predictive of attenuated response to ICS therapy. Hypothesis 3: Differences in response to ICS therapy between overweight/obese and lean asthmatics are due to GC insensitivity and/or systemic inflammation and not to baseline differences in asthma severity (as defined by physiologic, clinical or airway inflammatory characteristics). Associated specific aims will: 1) quantify the relationship between overweight/obesity and asthma severity in subjects with persistent asthma and 2) determine if overweight/obesity, when controlled for the degree of GC insensitivity and/or systemic inflammation, are predictive of attenuated response to ICS therapy. We anticipate this research will extend our understanding of mechanisms relating obesity and asthma while identifying modifiable factors or novel therapeutic strategies to optimize care for this growing proportion of asthma patients. Emerging evidence suggests a relationship between obesity and asthma, although the precise nature of this relationship is not known. We postulate that the systemic inflammatory state associated with obesity may have important biological effects on prognosis and response to therapy in asthma, in part by mediating the development of glucocorticoid insensitivity. We anticipate this research will extend our understanding of mechanisms relating obesity and asthma while identifying modifiable factors or novel therapeutic strategies to optimize care for this growing proportion of asthma patients. (End of Abstract)
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Obesity and asthma
    E Rand Sutherland
    National Jewish Medical and Research Center, Denver, CO 80206, USA
    Immunol Allergy Clin North Am 28:589-602, ix. 2008
  2. pmc Body mass and glucocorticoid response in asthma
    E Rand Sutherland
    Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, J 220 Denver, CO 80206, USA
    Am J Respir Crit Care Med 178:682-7. 2008
  3. ncbi Obesity and the lung: 4. Obesity and asthma
    D D Sin
    The Providence Heart and Lung Institute at St Paul s Hospital, Denver, CO, USA
    Thorax 63:1018-23. 2008
  4. pmc Cluster analysis of obesity and asthma phenotypes
    E Rand Sutherland
    Department of Medicine, National Jewish Health, Denver, Colorado, United States of America
    PLoS ONE 7:e36631. 2012
  5. pmc Obesity impairs apoptotic cell clearance in asthma
    Ruby Fernandez-Boyanapalli
    Department of Pediatrics, National Jewish Health, University of Colorado School of Medicine, Denver, CO 80206, USA
    J Allergy Clin Immunol 131:1041-7, 1047.e1-3. 2013
  6. pmc Vitamin D levels, lung function, and steroid response in adult asthma
    E Rand Sutherland
    Department of Medicine, University of Colorado, Denver, Colorado, USA
    Am J Respir Crit Care Med 181:699-704. 2010
  7. pmc A large subgroup of mild-to-moderate asthma is persistently noneosinophilic
    Kelly Wong McGrath
    Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA
    Am J Respir Crit Care Med 185:612-9. 2012

Scientific Experts

  • EVERETT SUTHERLAND
  • Ruby Fernandez-Boyanapalli
  • Kelly Wong McGrath
  • D D Sin
  • David W H Riches
  • Donald Y M Leung
  • Elysia Min
  • Donna L Bratton
  • Brian Day
  • Christena Kolakowski
  • Elena Goleva
  • Stephen C Lazarus
  • Homer A Boushey
  • Vernon M Chinchilli
  • Nikolina Icitovic
  • John V Fahy

Detail Information

Publications7

  1. pmc Obesity and asthma
    E Rand Sutherland
    National Jewish Medical and Research Center, Denver, CO 80206, USA
    Immunol Allergy Clin North Am 28:589-602, ix. 2008
    ..We evaluate animal studies that provide biological underpinnings to an association between the two disorders and clinical and epidemiologic studies that suggest that the relationship between these two disorders is clinically important...
  2. pmc Body mass and glucocorticoid response in asthma
    E Rand Sutherland
    Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, J 220 Denver, CO 80206, USA
    Am J Respir Crit Care Med 178:682-7. 2008
    ..Obesity may alter glucocorticoid response in asthma...
  3. ncbi Obesity and the lung: 4. Obesity and asthma
    D D Sin
    The Providence Heart and Lung Institute at St Paul s Hospital, Denver, CO, USA
    Thorax 63:1018-23. 2008
    ..This review examines the clinical and epidemiological relationship between obesity and asthma and the purported mechanisms that may link these two processes together...
  4. pmc Cluster analysis of obesity and asthma phenotypes
    E Rand Sutherland
    Department of Medicine, National Jewish Health, Denver, Colorado, United States of America
    PLoS ONE 7:e36631. 2012
    ..We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype...
  5. pmc Obesity impairs apoptotic cell clearance in asthma
    Ruby Fernandez-Boyanapalli
    Department of Pediatrics, National Jewish Health, University of Colorado School of Medicine, Denver, CO 80206, USA
    J Allergy Clin Immunol 131:1041-7, 1047.e1-3. 2013
    ..Asthma in obese adults is typically more severe and less responsive to glucocorticoids than asthma in nonobese adults...
  6. pmc Vitamin D levels, lung function, and steroid response in adult asthma
    E Rand Sutherland
    Department of Medicine, University of Colorado, Denver, Colorado, USA
    Am J Respir Crit Care Med 181:699-704. 2010
    ..Patients with asthma exhibit variable response to inhaled corticosteroids (ICS). Vitamin D is hypothesized to exert effects on phenotype and glucocorticoid (GC) response in asthma...
  7. pmc A large subgroup of mild-to-moderate asthma is persistently noneosinophilic
    Kelly Wong McGrath
    Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA
    Am J Respir Crit Care Med 185:612-9. 2012
    ....