Severe Asthma from Respiratory Infections

呼吸道感染引起的严重哮喘

• 批准号: 7287354
• 负责人: William W. Busse
• 金额: $ 58.49万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-20 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287354
• 关键词: Address; Adrenal Cortex Hormones; Affect; Anatomy; Anti-Infective Agents; Asthma; Biopsy; Breathing; Bronchoalveolar Lavage Fluid; CCL2 gene; Cells; Characteristics; Complex; Disease; Employee Strikes; Enrollment; Event; Figs - dietary; Generations; Growth; Growth Factor; Healthcare; IL8 gene; Image; Immune response; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferons; Interleukins; Irrigation; Lead; Lung; Mediator of activation protein; Morbidity - disease rate; Nose; Obstruction; Outcome; Patients; Pattern; Phase; Phenotype; Physiological; Physiology; Population; Protocols documentation; Pulmonary function tests; Recruitment Activity; Research Personnel; Respiratory System; Respiratory Tract Infections; Reverse Transcriptase Polymerase Chain Reaction; Rhinovirus; Sampling; Severities; Sputum; Structure; Symptoms; Technology; Testing; Triamcinolone; Viral; Viral Physiology; Virus; Work; airway epithelium; airway inflammation; base; chemokine; concept; cytokine; injured airway; insight; macrophage; microorganism; neutrophil; novel strategies; programs; repaired; respiratory; response

DESCRIPTION (provided by applicant): Although most patients are believed to have mild-to-moderate asthma that responds to inhaled corticosteroids, there are subpopulations of asthma patients with severe disease whose symptoms and control are largely unresponsive to treatment including systemic corticosteroids. Severe asthma affects 10% of all asthmatic subjects, but these patients have greater morbidity and a disproportionate need for health care support. The mechanisms of severe asthma are not determined, but respiratory infections cause the majority of asthma exacerbations and have profound and potentially long-lasting, effects on asthma including its severity and response to treatment. In attempting to evaluate mechanisms of severe asthma, striking similarities exist between features of severe asthma and the response to respiratory infections in asthma, including intensity of airflow obstruction, neutrophilic inflammation, and a diminished response to corticosteroids. These parallel features suggest that mechanisms of severe asthma may be related, at least in part, to similar events associated with respiratory infections. Rhinovirus infections have begun to emerge as principal contributors to many phases of asthma including inception and exacerbations and possibly severe asthma. It is speculated that respiratory infection effects on asthma severity are complex, multicellular and, in part, the result of a dysregulated immune response that allows RV to persist as an airway infection. Thus, it is hypothesized that severe asthma is caused, in some patients, by an infection with strains of rhinovirus resulting in changes in the airway milieu to create a phenotype shift in macrophages towards an alternatively activated population with reduced anti-viral actions to further a persistent infection, inflammation and obstruction. To test this hypothesis, the Systemic Triamcinolone in Asthma Characterization study will be applied to subjects with severe asthma compared to well-controlled asthma, to determine whether the differences are related to underlying corticosteroid therapy. The contribution of airway and parenchymal abnormalities to airflow limitation will be determined along with anatomic (imaging) changes in the lung, to correlate these changes with rhinovirus infections and inflammation. RT-PCR Multicode technology will be used to detect rhinovirus in respiratory tract samples and evaluate the effects of an infection on characteristics of severe asthma including inflammation through virus generation of cytokines and chemokines. Finally, the phenotype (classically activated vs. alternatively activated) and function (inflammatory vs. repair) of airway macrophages in severe asthma will be determined and their contribution to severe asthma determined. These studies will provide new insights into the mechanisms of asthma, particularly severe disease, and possibilities of new approaches to treatment.

描述（由申请人提供）： 尽管大多数患者被认为对吸入的皮质类固醇有反应的轻度至中度哮喘，但有一些严重疾病的哮喘患者的亚群，其症状和对照在很大程度上对包括全身性皮质类固醇的治疗无反应。严重的哮喘影响所有哮喘患者的10％，但是这些患者的发病率更高，对医疗保健支持的需求不成比例。严重哮喘的机制尚未确定，但是呼吸道感染会导致大多数哮喘加重，并且对哮喘的影响很大，并且具有严重的持久性，包括其严重程度和对治疗的反应。在尝试评估严重哮喘的机制时，严重哮喘的特征与对哮喘呼吸道感染的反应之间存在惊人的相似性，包括气流阻塞的强度，中性粒细胞炎症，以及对皮质激素的反应减少。这些平行特征表明，严重哮喘的机制至少部分与与呼吸道感染相关的类似事件有关。鼻病毒感染已开始成为哮喘许多阶段的主要贡献者，包括发动和加剧，可能是严重的哮喘。据推测，呼吸道感染对哮喘严重程度的影响是复杂的，多细胞的，部分是免疫反应失调的结果，该免疫反应使RV能够持续作为气道感染。因此，假设在某些患者中，引起严重的哮喘是通过鼻病毒菌株的感染导致气道环境变化的变化，从而在巨噬细胞中造成了巨噬细胞的表型转移向替代激活的人群，具有降低的抗病毒作用，以进一步持续感染，炎症和阻塞。为了检验这一假设，与控制良好的哮喘相比，哮喘特征研究中的全身性曲安赛将应用于严重哮喘的受试者，以确定差异是否与潜在的皮质类固醇治疗有关。气道和实质异常对气流限制的贡献将与肺部的解剖（成像）变化一起确定，以将这些变化与鼻病毒感染和炎症相关。 RT-PCR多模型技术将用于检测呼吸道样品中的鼻病毒，并评估感染对严重哮喘特征的影响，包括通过病毒的细胞因子和趋化因子的病毒产生炎症。最后，将确定严重哮喘中气道巨噬细胞的表型（经典激活与替代激活）和功能（炎症与修复），并确定它们对确定严重哮喘的贡献。这些研究将为哮喘的机制，尤其是严重疾病以及新方法的可能性提供新的见解。