These data indicate that in vitro biomarkers of GC insensitivity increase in both the lung and peripheral blood as body mass increases in individuals with asthma, but not in control subjects without asthma. This effect is manifested by reduced induction of MKP-1 expression in response to DEX in both PBMCs and BAL cells, and is related to enhanced expression of TNF-α in both peripheral and lung immune cells as body mass increases, suggesting a scenario in which one or more molecular pathways governing GC responses are modified in both the airway and peripheral blood in overweight and obese patients with asthma.
These findings are statistically robust, particularly with regard to the findings in PBMCs. Although our BAL data are restricted to a smaller subset of the participants with asthma, the sample facilitated detection of differences in the BAL that mirrored our findings in the peripheral blood, suggesting that the mechanisms underlying altered MKP-1 and TNF-α expression are operative in the lung as well. With regard to limitations of this work, it should be noted that subjects with asthma manifested a clinically significant degree of airflow limitation, suggesting that we have evaluated a population of patients with moderate-to-severe asthma, and raising the possibility that our findings may not apply to subjects with mild or intermittent asthma. This can also be interpreted as a potential strength, however, in that it provides observations likely to be relevant to a population of patients with asthma who are more challenging to manage. Our evaluation of molecular biomarkers related to GC response was focused on the MKP-1 pathway, and its potential modulation by TNF-α, allowing the possibility that other unmeasured mechanisms influencing GC signaling could also be operative in overweight and obese patients with asthma. Finally, because we relied on self-report of cigarette smoking, it is possible (although unlikely) that some subjects could have smoked during the study—a behavior known to modify oral GC response (24
As noted previously, the mechanisms by which obesity exerts its effects on asthma remain unclear (4
), although potential interactions other than an effect on response to therapy include an increased risk of developing asthma in the setting of obesity, or a skewing toward a more severe phenotype in the overweight or obese individual with asthma. A recent meta-analysis (2
) of prospective epidemiologic studies of BMI and asthma incidence indicated that overweight and obesity increase asthma incidence, with a statistically significant increase in the overall odds ratio for incident asthma in overweight and obese subjects to approximately 1.5, along with the suggestion of dose dependency in asthma risk as BMI increased, a phenomenon echoed in the findings of this study with regard to GC response. Studies of the relationship between BMI and asthma in patients with prevalent asthma are less common, but a recent report from the National Heart, Lung, and Blood Institute–funded Severe Asthma Research Program (25
) indicated that, in approximately 250 subjects with severe asthma (26
), obesity was not more prevalent in severe versus moderate asthma, leading to questions about the role of obesity as a modifier of asthma severity.
Most relevant to our data is the possibility that the inflammatory environment in obesity modifies either clinical or biologic response to GCs. In obesity, enhancement of normal adipose tissue immune function leads to a systemic inflammatory state (5
), and many of the cytokines found to be elevated in obesity-related systemic inflammation are also associated with development of GC insensitivity in asthma (8
), and may be critical components of the mechanisms by which this phenomenon occurs in overweight and obese patients with asthma. The mechanisms of GC insensitivity are complex, reflecting the multiple steps involved in GC action, but most important with regard to our findings are the effects of MAPK activation on GC receptor function. Phosphorylation modulates the function of the GC receptor (27
), and prior studies have demonstrated that cytokine-induced phosphorylation of the GC receptor, mediated by p38 MAPK or other pathways, is associated with loss of GCR nuclear translocation and reduced responsiveness of T cells to DEX (29
). GCs have also been reported to increase expression of a key regulator of MAPK inactivation, MKP-1 (14
). The observed attenuation of MKP-1 expression in overweight and obese patients with asthma may allow persistent MAPK activation (14
), thereby reducing molecular response to GCs and resulting in an associated reduced clinical response to these agents.
Research over the last decade has demonstrated that TNF-α is overexpressed in the adipose tissue and muscle of obese humans (33
), a phenomenon that may be of relevance to the treatment of patients with GC-insensitive asthma, both with regard to the potential impact on MAPK signaling pathways noted in the Introduction
, and with regard to the findings of the recent clinical trial by Berry and colleagues, which demonstrated an increase in expression of membrane-bound TNF-α, TNF-α receptor 1, and TNF-α–converting enzyme in PBMCs from patients with severe asthma, in which clinical surrogates of GC insensitivity are the major defining criteria (26
). This study demonstrated a beneficial effect of soluble TNF-α receptor etanercept in these patients, as shown by improvements in airway hyperresponsiveness, FEV1
, and asthma-related quality of life (37
), raising the possibility that controller agents other than corticosteroids may be more appropriate for patients with asthma characterized by obesity and GC insensitivity. Although our data are not conclusive, they do suggest that increased TNF-α in overweight and obese patients with asthma might be one signal by which down-regulation of MKP-1 expression is controlled.
Additional clinical and basic research is necessary to elucidate the mechanisms by which overweight and obesity modify response to GC therapy in asthma, and we suggest that our research has identified but one potential mechanism by which obesity could alter response to controller therapy in asthma. Recognition of this phenomenon may help identify asthma patients at risk for suboptimal response to controller therapy over the long term, and lead to the development of alternative effective strategies for this prevalent subgroup of patients with asthma.