Obesity, Inflammation and Response to Therapy in Asthma

肥胖、炎症和哮喘治疗反应

• 批准号: 7355946
• 负责人: EVERETT RAND SUTHERLAND
• 金额: $ 35.79万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7355946
• 关键词: Adrenal Cortex Hormones; Ancillary Study; Asthma; Attenuated; Biological; Biological Markers; Breathing; Caring; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Complement 2; Development; Glucocorticoids; Immunologics; Impairment; Individual; Inflammation; Inflammatory; Interleukin-6; Interleukins; Leptin; Mediating; Nature; Obesity; Overweight; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Process; Research; Risk; Severities; Sputum; TNF gene; Testing; Time; Tumor Necrosis Factor-alpha; Weight; abstracting; airway inflammation; base; cysteine rich protein; cytokine; novel therapeutics; outcome forecast; response

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)

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气道炎症或生理损伤，从而增加哮喘发作的风险或导致更严重的哮喘表型，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产生的，而是通过改变气道炎症来实现的。相反，通过相关的全身炎症过程减弱对控制疗法（例如吸入皮质类固醇）的反应。初步研究表明超重和肥胖哮喘患者对糖皮质激素（GC）不敏感和全身炎症，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产生重要的生物学影响，部分原因是介导 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测试以下相互关联的假设，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（“瘦哮喘患者”）更有可能出现症状气相色谱不敏感。相关的具体目标将确定：1) 超重/肥胖与瘦哮喘患者的外周血单核细胞 (PBMC) 对 GC 的免疫反应，2) 来自这些组的诱导痰细胞中 GC 不敏感的生物标志物的表达，以及 3) 如果GC 不敏感预示着吸入皮质类固醇 (ICS) 治疗的反应减弱。假设2：超重/肥胖哮喘患者比瘦哮喘患者更有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-α）和其他促炎细胞因子的表达增加，并导致GC不敏感。相关的具体目标将确定：1) 与瘦哮喘患者相比，超重/肥胖患者的细胞因子和其他全身炎症生物标志物（IL-6、TNF-α、瘦素、CRP）是否增加，2) 细胞因子和其他全身炎症生物标志物是否增加发现在超重/肥胖哮喘患者中升高，降低 GC 敏感哮喘患者 PBMC 的 GC 敏感性，3) 确定全身炎症的生物标志物是否可预测 ICS 反应减弱 治疗。假设 3：超重/肥胖和瘦哮喘患者对 ICS 治疗的反应差异是由于 GC 不敏感和/或全身炎症所致，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）量化持续性哮喘受试者的超重/肥胖与哮喘严重程度之间的关系，2）确定在控制GC不敏感和/或全身炎症程度时，超重/肥胖是否可以预测反应减弱ICS 治疗。我们预计这项研究将加深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，以优化对日益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。我们假设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产生重要的生物学影响，部分是通过介导糖皮质激素不敏感的发展来实现的。我们预计这项研究将加深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，以优化对日益增长的哮喘患者比例的护理。 （摘要完）