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）： 新兴的证据表明肥胖与哮喘之间存在关系，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障碍，从而升高出现哮喘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SE中的呼吸道炎症改变来施加的，而是通过相关的系统性炎症过程来促进响应的响应。在初步研究的基础上，表明超重和肥胖哮喘患者中糖皮质激素（GC）不敏感和全身性炎症的证据，我们假设与肥胖相关的全身性炎症状态可能对哮喘的预后和对治疗的反应具有重要的生物学作用，部分地通过培养GC稳固性的发展。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2个即将进行的哮喘临床研究网络的临床试验：假设1：超重/肥胖/肥胖的哮喘患者比正常体重的哮喘患者更有可能（“瘦心性行为”），以表现出GC的表现。 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.假设2：超重/肥胖的哮喘患者比瘦哮喘患者更有可能证明全身性炎症，从而导致白介素（IL）-6，肿瘤坏死因子 - α（TNF-？）和其他促炎细胞因子和其他促炎细胞因子的表达增加，并导致GC不敏感。相关的特定目的将确定：1）超重/肥胖与瘦哮喘患者中的细胞因子和其他全身炎症（IL-6，TNF-？，瘦素，CRP）的增加是否会增加，2）如果细胞因子和其他系统炎症的生物标志物在全身性炎症中被发现升高/肥胖症的GC级别GC级别的GC级别GC升高，哮喘患者和3）确定系统性炎症的生物标志物是否可以预测对ICS治疗的反应减弱。假设3：超重/肥胖和瘦哮喘患者之间对ICS治疗的反应差异是由于GC不敏感性和/或全身性炎症引起的，而不是哮喘染色的基线差异（如生理，临床或气道炎症特征所定义）。相关的特定目的将：1）量化持续性哮喘的受试者中的超重/肥胖症和哮喘严重程度之间的关系，2）确定在控制GC不敏感性和/或全身性炎症程度时，是否超重/肥胖是对ICS治疗的衰减反应的预测。我们预计，这项研究将扩展我们对肥胖和哮喘相关的机制的理解，同时确定可修改的因素或新颖的治疗策略，以优化不断增长的哮喘患者的护理。新兴的证据表明肥胖与哮喘之间存在关系，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性炎症状态可能对哮喘的预后和对治疗的反应具有重要的生物学作用，部分原因是介导糖皮质激素不敏感性的发展。我们预计，这项研究将扩展我们对肥胖和哮喘相关的机制的理解，同时确定可修改的因素或新颖的治疗策略，以优化不断增长的哮喘患者的护理。 （抽象的结尾）