Obesity, Inflammation and Response to Therapy in Asthma

描述(由申请人提供)： 新出现的证据表明，肥胖和哮喘之间存在关系，尽管这种关系的确切性质尚不清楚。虽然肥胖可能会增加呼吸道炎症或生理损伤，从而增加哮喘发生的风险或导致更严重的哮喘表型，但也有可能肥胖对哮喘患者的影响不是通过呼吸道炎症本身的变化，而是通过相关的全身炎症过程来减弱对控制性治疗(如吸入皮质类固醇)的反应。根据超重和肥胖哮喘患者存在糖皮质激素(GC)不敏感和全身炎症的初步研究，我们推测与肥胖相关的全身炎症状态可能对哮喘的预后和治疗反应有重要的生物学影响，部分是通过介导GC不敏感的发展。我们建议在一项时间敏感的辅助研究中测试以下相关假设，该研究补充了哮喘临床研究网络即将进行的两项临床试验：假设1：超重/肥胖的哮喘患者比正常体重的哮喘患者(“瘦哮喘患者”)更有可能表现出GC不敏感。相关的特定目标将决定：1)超重/肥胖与瘦哮喘患者外周血单个核细胞(PBMC)对GC的免疫反应，2)这些组诱导痰细胞中GC不敏感生物标志物的表达，以及3)GC不敏感生物标志物是否预测吸入皮质类固醇(ICS)治疗的减弱反应。假设2：超重/肥胖哮喘患者比瘦哮喘患者更容易出现全身炎症，导致白细胞介素6、肿瘤坏死因子-α的表达增加。和其他促炎细胞因子，并导致GC不敏感。相关的特定目标将决定：1)细胞因子和其他全身炎症生物标志物(IL-6、肿瘤坏死因子-1、瘦素、C反应蛋白)在超重/肥胖哮喘患者与瘦哮喘患者相比是否增加，2)细胞因子和其他全身炎症生物标志物在超重/肥胖哮喘患者中是否升高，降低GC敏感型哮喘患者PBMC对GC的敏感性，以及3)确定全身炎症生物标志物是否预测ICS治疗的反应减弱。假设3：超重/肥胖和瘦型哮喘患者对ICS治疗的反应差异是由于GC不敏感和/或全身炎症，而不是由于哮喘严重程度的基线差异(由生理、临床或呼吸道炎症特征定义)。相关的特定目标将：1)量化持续哮喘患者中超重/肥胖与哮喘严重程度之间的关系，以及2)确定超重/肥胖在控制GC不敏感和/或全身炎症的程度后，是否预示着ICS疗法的反应减弱。我们预计这项研究将扩大我们对肥胖和哮喘相关机制的理解，同时确定可修改的因素或新的治疗策略，以优化对这一比例不断增长的哮喘患者的护理。新出现的证据表明，肥胖和哮喘之间存在关系，尽管这种关系的确切性质尚不清楚。我们推测，与肥胖相关的全身炎症状态可能对哮喘的预后和治疗反应有重要的生物学影响，部分是通过调节糖皮质激素不敏感的发展而实现的。我们预计这项研究将扩大我们对肥胖和哮喘相关机制的理解，同时确定可修改的因素或新的治疗策略，以优化对这一比例不断增长的哮喘患者的护理。(摘要结束)

DESCRIPTION (provided by applicant): 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)