Body Mass and Glucocorticoid Response in Asthma

Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, J-220 Denver, CO 80206, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 10/2008; 178(7):682-7. DOI: 10.1164/rccm.200801-076OC
Source: PubMed


Obesity may alter glucocorticoid response in asthma.
To evaluate the relationship between body mass index (BMI, kg/m(2)) and glucocorticoid response in subjects with and without asthma.
Nonsmoking adult subjects underwent characterization of lung function, BMI, and spirometric response to prednisone. Dexamethasone (DEX, 10(-6) M)-induced mitogen-activated protein kinase phosphatase-1 (MKP-1) and baseline tumor necrosis factor (TNF)-alpha expression were evaluated by polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) and bronchoalveolar lavage cells. The relationship between BMI and expression of MKP-1 and TNF-alpha was analyzed.
A total of 45 nonsmoking adults, 33 with asthma (mean [SD] FEV(1)% of 70.7 [9.8]%) and 12 without asthma were enrolled. DEX-induced PBMC MKP-1 expression was reduced in overweight/obese versus lean patients with asthma, with mean (+/- SEM) fold-induction of 3.11 (+/-0.46) versus 5.27 (+/-0.66), respectively (P = 0.01). In patients with asthma, regression analysis revealed a -0.16 (+/-0.08)-fold decrease in DEX-induced MKP-1 per unit BMI increase (P = 0.04). PBMC TNF-alpha expression increased as BMI increased in subjects with asthma, with a 0.27 unit increase in log (TNF-alpha [ng/ml]) per unit BMI increase (P = 0.01). The ratio of PBMC log (TNF-alpha):DEX-induced MKP-1 also increased as BMI increased in patients with asthma (+0.09 +/- 0.02; P = 0.004). In bronchoalveolar lavage cells, DEX-induced MKP-1 expression was also reduced in overweight/obese versus lean patients with asthma (1.36 +/- 0.09-fold vs. 1.76 +/- 0.15-fold induction; P = 0.05). Similar findings were not observed in control subjects without asthma.
Elevated BMI is associated with blunted in vitro response to dexamethasone in overweight and obese patients with asthma.

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    • "Not only is obesity a risk factor for asthma, but asthma in the obese has distinct features compared to disease in the non-obese. Obese asthmatics tend to have more severe disease [2] [3] respond less well to standard controller therapy, [4] and have evidence of cellular glucocorticoid resistance [5]. This despite the fact they do not appear to have worsened airway inflammation as measured by either sputum eosinophils or neutrophils [6]. "
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    ABSTRACT: Asthma in the obese represents a growing epidemic of pulmonary disease, and these patients are distinct from non obese asthmatics. Accordingly, studies on the pathogenesis of asthma in the obese are critical to guide our understanding of this disease process; such studies will ultimately guide the development of new therapies to treat the obese asthmatic population.
    03/2015; 41(3). DOI:10.1016/j.ejcdt.2015.02.012
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    • "Obese asthmatic patients are often described as severe and poorly controlled4,5 perhaps because they are less responsive to corticosteroids and exhibit a different (e.g., less atopic) inflammatory phenotype.6 Obesity is associated with chronic low-grade systemic inflammation that is thought to enhance systemic complications.7 It is known that adipose tissue can regulate systemic inflammation through the production of a variety of adipokines which may link the two disorders mechanistically.8 "
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    ABSTRACT: Increasing epidemiological data identify a link between obesity and asthma incidence and severity. Based on experimental data, it is possible that shared inflammatory mechanisms play a role in determining this linkage. Although controversial, the role of adipokines may be central to this association and the maintenance of the asthma phenotype. While leptin and adiponectin have a causal link to experimental asthma in mice, data in humans are less conclusive. Recent studies demonstrate that adipokines can regulate the survival and function of eosinophils and that these factors can affect eosinophil trafficking from the bone marrow to the airways. In addition, efferocytosis, the clearance of dead cells, by airway macrophages or blood monocytes appears impaired in obese asthmatics and is inversely correlated with glucocorticoid responsiveness. This review examines the potential mechanisms linking obesity to asthma.
    Allergy, asthma & immunology research 05/2014; 6(3):189-195. DOI:10.4168/aair.2014.6.3.189 · 2.43 Impact Factor
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    • "Obesity and weight gain are considered risk factors for asthma exacerbations [2]. Obese asthmatic patients exhibit worse asthma control [3] and do not respond properly to standard therapy as lean asthmatic patients [4,5]. Studies show that IR accounts for most of the obesity-associated asthma risk in children and adults [2,6]. "
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    ABSTRACT: A positive relationship between obesity and asthma has been well documented. The AMP-activated protein kinase (AMPK) activator metformin reverses obesity-associated insulin resistance (IR) and inhibits different types of inflammatory responses. This study aimed to evaluate the effects of metformin on the exacerbation of allergic eosinophilic inflammation in obese mice. Male C57BL6/J mice were fed for 10 weeks with high-fat diet (HFD) to induce obesity. The cell infiltration and inflammatory markers in bronchoalveolar lavage (BAL) fluid and lung tissue were evaluated at 48 h after ovalbumin (OVA) challenge. HFD obese mice displayed peripheral IR that was fully reversed by metformin (300 mg/kg/day, two weeks). OVA-challenge resulted in higher influx of total cell and eosinophils in lung tissue of obese mice compared with lean group. As opposed, the cell number in BAL fluid of obese mice was reduced compared with lean group. Metformin significantly reduced the tissue eosinophil infiltration and prevented the reduction of cell counts in BAL fluid. In obese mice, greater levels of eotaxin, TNF-α and NOx, together with increased iNOS protein expression were observed, all of which were normalized by metformin. In addition, metformin nearly abrogated the binding of NF-κB subunit p65 to the iNOS promoter gene in lung tissue of obese mice. Lower levels of phosphorylated AMPK and its downstream target acetyl CoA carboxylase (ACC) were found in lung tissue of obese mice, which were restored by metformin. In separate experiments, the selective iNOS inhibitor aminoguanidine (20 mg/kg, 3 weeks) and the anti-TNF-α mAb (2 mg/kg) significantly attenuated the aggravation of eosinophilic inflammation in obese mice. In conclusion, metformin inhibits the TNF-α-induced inflammatory signaling and NF-κB-mediated iNOS expression in lung tissue of obese mice. Metformin may be a good pharmacological strategy to control the asthma exacerbation in obese individuals.
    PLoS ONE 10/2013; 8(10):e76786. DOI:10.1371/journal.pone.0076786 · 3.23 Impact Factor
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