Abstract
Asthma in obese adults is more severe than in lean individuals, and emerging data from clinical and translational studies suggest that obese patients are also less likely to respond to controller therapies, particularly inhaled corticosteroids. As a result, obese asthmatics receive complicated treatment regimens to which they are less likely to respond favorably. Given the high prevalence of both asthma and obesity, this interaction has significant potential to adversely impact both individual and population asthma burden. Despite this, no specific guidance currently exists in NIH or international guidelines as to the optimal therapeutic approach to the obese asthmatic. This chapter will review clinical data regarding mechanisms by which obesity modifies asthma phenotype, focusing on clinical and translational studies of response to controller therapies such as glucocorticoids and agents targeting leukotriene pathways.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178:218–24.
Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2009;181:315–23.
Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY. Vitamin D levels, lung function, and steroid response in adult asthma. Am J Respir Crit Care Med. 2010;181:699–704.
Sutherland ER, Goleva E, Strand M, Beuther DA, Leung DY. Body mass and glucocorticoid response in asthma. Am J Respir Crit Care Med. 2008;178:682–7.
Sutherland ER, Lehman EB, Teodorescu M, Wechsler ME. Body mass index and phenotype in subjects with mild-to-moderate persistent asthma. J Allergy Clin Immunol. 2009;123:1328–34. e1.
Expert panel report 3: guidelines for the diagnosis and management of asthma. U.S. Department of Health and Human Services 2007. NIH Publication Number 07–4051.
Global strategy for asthma management and prevention 2008 update. http://www.ginasthma.org. Accessed 1 Nov 2011.
Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.
Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995;95:2409–15.
Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993;259:87–91.
Beuther DA, Weiss ST, Sutherland ER. Obesity and asthma. Am J Respir Crit Care Med. 2006;174:112–9.
Cottrell L, Neal WA, Ice C, Perez MK, Piedimonte G. Metabolic abnormalities in children with asthma. Am J Respir Crit Care Med. 2011;183:441–8.
Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest. 2008;134:394–401.
Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, et al. Can guideline-defined asthma control be achieved? The gaining optimal asthma control study. Am J Respir Crit Care Med. 2004;170:836–44.
Szefler SJ, Martin RJ, King TS, Boushey HA, Cherniack RM, Chinchilli VM, et al. Significant variability in response to inhaled corticosteroids for persistent asthma. J Allergy Clin Immunol. 2002;109:410–8.
Leung DY, Bloom JW. Update on glucocorticoid action and resistance. J Allergy Clin Immunol. 2003;111:3–22.
Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. 2000;20:6891–903.
Matthews JG, Ito K, Barnes PJ, Adcock IM. Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients. J Allergy Clin Immunol. 2004;113:1100–8.
Clark AR. MAP kinase phosphatase 1: a novel mediator of biological effects of glucocorticoids? J Endocrinol. 2003;178:5–12.
Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, Cato AC. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J. 2001;20:7108–16.
Zhao Q, Shepherd EG, Manson ME, Nelin LD, Sorokin A, Liu Y. The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. J Biol Chem. 2005;280:8101–8.
Chung KF. p38 Mitogen-Activated protein kinase pathways in asthma and COPD. Chest. 2011;139:1470–9.
Bamberger CM, Bamberger AM, de Castro M, Chrousos GP. Glucocorticoid receptor beta, a potential endogenous inhibitor of glucocorticoid action in humans. J Clin Invest. 1995;95:2435–41.
Oakley RH, Webster JC, Sar M, Parker Jr CR, Cidlowski JA. Expression and subcellular distribution of the beta-isoform of the human glucocorticoid receptor. Endocrinology. 1997;138:5028–38.
Oakley RH, Jewell CM, Yudt MR, Bofetiado DM, Cidlowski JA. The dominant negative activity of the human glucocorticoid receptor beta isoform. Specificity and mechanisms of action. J Biol Chem. 1999;274:27857–66.
Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem. 1996;271:9550–9.
Yudt MR, Jewell CM, Bienstock RJ, Cidlowski JA. Molecular origins for the dominant negative function of human glucocorticoid receptor beta. Mol Cell Biol. 2003;23:4319–30.
Webster JC, Oakley RH, Jewell CM, Cidlowski JA. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci USA. 2001;98:6865–70.
Leung DY, Hamid Q, Vottero A, Szefler SJ, Surs W, Minshall E, et al. Association of glucocorticoid insensitivity with increased expression of glucocorticoid receptor beta. J Exp Med. 1997;186:1567–74.
Goleva E, Li LB, Eves PT, Strand MJ, Martin RJ, Leung DY. Increased glucocorticoid receptor beta alters steroid response in glucocorticoid-insensitive asthma. Am J Respir Crit Care Med. 2006;173:607–16.
Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111–9.
Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Invest. 1995;95:2111–9.
Krogh-Madsen R, Plomgaard P, Moller K, Mittendorfer B, Pedersen BK. Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans. Am J Physiol Endocrinol Metab. 2006;291:E108–14.
Saghizadeh M, Ong JM, Garvey WT, Henry RR, Kern PA. The expression of TNF alpha by human muscle. Relationship to insulin resistance. J Clin Invest. 1996;97:1111–6.
Cote M, Mauriege P, Bergeron J, Almeras N, Tremblay A, Lemieux I, et al. Adiponectinemia in visceral obesity: impact on glucose tolerance and plasma lipoprotein and lipid levels in men. J Clin Endocrinol Metab. 2005;90:1434–9.
Lemieux I, et al. Contribution of interleukin-6 and tumor necrosis factor-alpha to the elevated C-reactive protein levels found in abdominally obese men. Obes Res. 2001;9:66S.
Hauk PJ, Goleva E, Liu AH, et al. Corticosteroid resistant asthma is associated with classical activation of airway macrophages and exposure to lipopolysaccharide. J Allergy Clin Immunol. 2006;117:S194.
Vortmann M, Eisner MD. BMI and health status among adults with asthma. Obesity (Silver Spring). 2008;16:146–52.
Todd DC, Armstrong S, D’Silva L, Allen CJ, Hargreave FE, Parameswaran K. Effect of obesity on airway inflammation: a cross-sectional analysis of body mass index and sputum cell counts. Clin Exp Allergy. 2007;37:1049–54.
McLachlan CR, Poulton R, Car G, Cowan J, Filsell S, Greene JM, et al. Adiposity, asthma, and airway inflammation. J Allergy Clin Immunol. 2007;119:634–9.
Lee YH, Nair S, Rousseau E, Allison DB, Page GP, Tataranni PA, et al. Microarray profiling of isolated abdominal subcutaneous adipocytes from obese vs non-obese Pima Indians: increased expression of inflammation-related genes. Diabetologia. 2005;48:1776–83.
Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest. 2006;116:1494–505.
Dahlman I, Kaaman M, Olsson T, Tan GD, Bickerton AS, Wahlen K, et al. A unique role of monocyte chemoattractant protein 1 among chemokines in adipose tissue of obese subjects. J Clin Endocrinol Metab. 2005;90:5834–40.
Gordon S. Macrophage heterogeneity and tissue lipids. J Clin Invest. 2007;117:89–93.
Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. 2007;117:175–84.
Ghanim H, Aljada A, Hofmeyer D, Syed T, Mohanty P, Dandona P. Circulating mononuclear cells in the obese are in a proinflammatory state. Circulation. 2004;110:1564–71.
Gustafson B, Smith U. Cytokines promote Wnt signaling and inflammation and impair the normal differentiation and lipid accumulation in 3 T3-L1 preadipocytes. J Biol Chem. 2006;281:9507–16.
Powell K. Obesity: the two faces of fat. Nature. 2007;447:525–7.
Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.
Duffield JS. The inflammatory macrophage: a story of Jekyll and Hyde. Clin Sci (Lond). 2003;104:27–38.
Van Ginderachter JA, Movahedi K, Hassanzadeh Ghassabeh G, Meerschaut S, Beschin A, Raes G, et al. Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology. 2006;211:487–501.
Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol. 2006;177:7303–11.
Zimmermann N, King NE, Laporte J, Yang M, Mishra A, Pope SM, et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest. 2003;111:1863–74.
Truyen E, Coteur L, Dilissen E, Overbergh L, Dupont LJ, Ceuppens JL, et al. Evaluation of airway inflammation by quantitative Th1/Th2 cytokine mRNA measurement in sputum of asthma patients. Thorax. 2006;61:202–8.
Arshad SH, Kurukulaaratchy RJ, Fenn M, Matthews S. Early life risk factors for current wheeze, asthma, and bronchial hyperresponsiveness at 10 years of age. Chest. 2005;127:502–8.
Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006;354:697–708.
Hauk PJ, Goleva E, Liu AH, Hall CF, Riches DWH, Martin RJ, et al. Corticosteroid resistant (CR) asthma is associated with classical activation of airway macrophages and exposure to lipopolysaccharide (LPS). J Allergy Clin Immunol. 2006;117:S194.
Hakonarson H, Bjornsdottir US, Halapi E, Bradfield J, Zink F, Mouy M, et al. Profiling of genes expressed in peripheral blood mononuclear cells predicts glucocorticoid sensitivity in asthma patients. Proc Natl Acad Sci USA. 2005;102:14789–94.
Peters-Golden M, Swern A, Bird SS, Hustad CM, Grant E, Edelman JM. Influence of body mass index on the response to asthma controller agents. Eur Respir J. 2006;27:495–503.
Bateman ED. Can guideline-defined asthma control be achieved?: the gaining optimal asthma control study. Am J Respir Crit Care Med. 2004;170:836–44.
Obesity: preventing and managing the global epidemic. Report of a WHO consultation. World Health Organ Tech Rep Ser. 2000;894:i–xii, 1–253.
Boulet L, Franssen E. Influence of obesity on response to fluticasone with or without salmeterol in moderate asthma. Respir Med. 2007;101:2240–7.
Camargo CA, Boulet L-P, Sutherland ER, Busse WW, Yancey SW, Emmett AH, et al. Body mass index and response to asthma therapy: fluticasone propionate/salmeterol versus montelukast. J Asthma. 2010;47:76–82.
Camargo Jr CA, Sutherland ER, Bailey W, Castro M, Yancey SW, Emmett AH, et al. Effect of increased body mass index on asthma risk, impairment and response to asthma controller therapy in African Americans. Curr Med Res Opin. 2010;26:1629–35.
Sutherland ER, Camargo CA, Busse WW, Meltzer EO, Ortega HG, Yancey SW, et al. Comparative effect of body mass index on response to asthma controller therapy. Allergy Asthma Proc. 2010;31:20–5.
Dixon AE, Shade DM, Cohen RI, Skloot GS, Holbrook JT, Smith LJ, et al. Effect of obesity on clinical presentation and response to treatment in asthma. J Asthma. 2006;43:553–8.
Forno E, Lescher R, Strunk R, Weiss S, Fuhlbrigge A, Celedon JC. Decreased response to inhaled steroids in overweight and obese asthmatic children. J Allergy Clin Immunol. 2011;127:741–9.
Kattan M, Kumar R, Bloomberg GR, Mitchell HE, Calatroni A, Gergen PJ, et al. Asthma control, adiposity, and adipokines among inner-city adolescents. J Allergy Clin Immunol. 2010;125:584–92.
Eckel RH. Clinical practice. Nonsurgical management of obesity in adults. N Engl J Med. 2008;358:1941–50.
Poirier P, Giles T, Bray G, Hong Y, Stern J, Pi-Sunyer F, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific statement on obesity and heart disease from the obesity committee of the council on nutrition, physical activity, and metabolism. Circulation. 2006;113:898.
Dixon AE, Pratley RE, Forgione PM, Kaminsky DA, Whittaker-Leclair LA, Griffes LA, et al. Effects of obesity and bariatric surgery on airway hyperresponsiveness, asthma control, and inflammation. J Allergy Clin Immunol. 2011;128:508–15.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Sutherland, E.R. (2013). Treatment of the Obese Patient with Asthma. In: Dixon, A., Clerisme-Beaty, E. (eds) Obesity and Lung Disease. Respiratory Medicine, vol 19. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-053-3_7
Download citation
DOI: https://doi.org/10.1007/978-1-62703-053-3_7
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-052-6
Online ISBN: 978-1-62703-053-3
eBook Packages: MedicineMedicine (R0)