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。虽然肥胖可能增加气道炎症或生理损害，从而增加哮喘发作的风险或引起更严重的哮喘表型，但肥胖对哮喘患者的影响也可能不是通过气道炎症本身的改变，而是通过相关的全身炎症过程来发挥作用，这些炎症过程减弱了对控制治疗（如吸入性皮质类固醇）的反应。在初步研究表明超重和肥胖哮喘患者存在糖皮质激素（GC）不敏感性和全身炎症的证据的基础上，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具有重要的生物学效应，部分是通过介导GC不敏感性的发展。我们建议在一项时间敏感的辅助研究中检验以下相关假设，以补充哮喘临床研究网络即将进行的2项临床试验：假设1：超重/肥胖哮喘患者比正常体重的哮喘患者（"瘦型哮喘患者"）更可能表现出GC不敏感性。相关的具体目的将确定：1）来自超重/肥胖与瘦型哮喘患者的外周血单核细胞（PBMC）对GC的免疫应答，2）来自这些组的诱导痰细胞中GC不敏感性的生物标志物的表达，以及3）GC不敏感性的生物标志物是否预测对吸入性皮质类固醇（ICS）治疗的减弱应答。假设二：超重/肥胖哮喘患者比瘦型哮喘患者更可能表现出全身炎症，导致白细胞介素（IL）-6、肿瘤坏死因子-α（TNF-？）和其他促炎细胞因子并导致GC不敏感。相关的具体目标将确定：1）是否有细胞因子和全身性炎症的其他生物标志物（IL-6，TNF-β，瘦素，CRP）在超重/肥胖哮喘患者中相对于瘦型哮喘患者增加，2）如果发现在超重/肥胖哮喘患者中升高的细胞因子和全身炎症的其它生物标志物降低来自GC敏感性哮喘患者的PBMC的GC敏感性，和3）确定全身炎症的生物标志物是否预示对ICS治疗的减弱的反应。假设三：超重/肥胖和瘦型哮喘患者对ICS治疗反应的差异是由于GC不敏感和/或全身炎症，而不是哮喘严重程度的基线差异（由生理、临床或气道炎症特征定义）。相关的具体目标将：1）量化患有持续性哮喘的受试者中超重/肥胖与哮喘严重程度之间的关系，和2）确定当控制GC不敏感性和/或全身炎症的程度时，超重/肥胖是否预测对ICS治疗的减弱反应。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，同时确定可改变的因素或新的治疗策略，以优化对这一不断增长的哮喘患者比例的护理。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，肥胖相关的全身炎症状态可能对哮喘的预后和治疗反应具有重要的生物学效应，部分是通过介导糖皮质激素不敏感性的发展。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，同时确定可改变的因素或新的治疗策略，以优化对这一不断增长的哮喘患者比例的护理。(End摘要）

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)