Airway Cellular and Cytokine Profiles in Older Patients with Asthma

老年哮喘患者的气道细胞和细胞因子谱

• 批准号: 8716660
• 负责人: PAULA J BUSSE
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-08 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716660
• 关键词: Address; Adrenal Cortex Hormones; Adult asthma; Affect; Age; Aging; Antibody Formation; Asthma; Body Weight decreased; Breathing; Cell Count; Cell physiology; Cells; Child; Comorbidity; Data; Dendritic Cells; Dose; Elderly; Functional disorder; Generations; Goals; Health; Human; IgE; Immunophenotyping; Infection; Inflammation; Inflammatory; Inflammatory Response; Influenza; Interleukin-10; Interleukin-17; Interleukin-6; Modeling; Morbidity - disease rate; Mus; Neutrophilia; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Play; Process; Recruitment Activity; Regimen; Regulation; Regulatory T-Lymphocyte; Research; Respiratory Tract Infections; Risk; Role; Severities; Severity of illness; Specificity; Sputum; Standardization; T-Cell Receptor; T-Lymphocyte; TNF gene; Testing; Translating; Vaccination; age effect; age group; age related; aged; airway hyperresponsiveness; airway inflammation; cytokine; effective therapy; ethnic minority population; high risk; immune function; indexing; innate immune function; mortality; neutrophil; normal aging; older patient; oral tolerance; peripheral blood; response; treatment response; young adult

DESCRIPTION (provided by applicant): The recognition of distinct asthma phenotypes has begun to explain differences in disease severity, persistence and response to treatment in children and younger adults. Emerging data suggest that aging also has an important effect on asthma; older asthmatics have greater morbidity and mortality, possibly reflecting distinct underlying pathophysiology and variable treatment responses. While mechanisms underlying these changes in older asthmatics are not well established, age-related alterations in immune function likely play an important role. To define the effects of age on key features of asthma, airway inflammation and airway hyperresponsiveness (AHR), we first developed a murine model of asthma using Ag sensitization and airway challenge in younger and older mice. Distinct patterns of airway inflammatory responses to Ag challenge were found in older mice characterized by increased IL-6, IL-10, IL-17, TGF-¿ expression and greater numbers of airway neutrophils and Treg cells. To translate our murine findings to humans we next generated preliminary data which suggest enhanced formation of IL-6 and neutrophilia are important to the pathophysiology of asthma in older subjects. We therefore hypothesize that, compared to younger asthmatics, older asthmatics will manifest a distinct inflammatory phenotype indexed by increased generation of IL-6, which, in turn, increases the expression of Th17 cells to induce airway neutrophilia, and also decreases Treg cell function. To test our hypothesis we will collect induced sputum and peripheral blood from 40 older (>60 years) and 40 younger adult (21-40 years) asthmatics (receiving a standardized low dose of inhaled corticosteroids) and 80 age-matched controls. We will then: a) establish the airway inflammatory (cytokine and cellular) phenotypes in the older asthmatic subjects in comparison to younger adult asthma subjects and examine association with asthma control, and b) investigate whether IL-6 contributes to the mechanisms of asthma in the older subjects by enhancing Th17 expression and decreasing Treg function.

描述（由申请人提供）：对不同哮喘表型的认识已开始解释儿童和年轻成人疾病严重程度、持续性和治疗反应的差异。 新出现的数据表明，衰老也对哮喘有重要影响;老年哮喘患者的发病率和死亡率更高，这可能反映了不同的潜在病理生理学和可变的治疗反应。虽然老年哮喘患者发生这些变化的机制尚未完全确定，但与年龄相关的免疫功能改变可能起着重要作用。 为了确定年龄对哮喘、气道炎症和气道高反应性（AHR）的关键特征的影响，我们首先在年轻和老年小鼠中使用Ag致敏和气道激发建立了哮喘小鼠模型。在年龄较大的小鼠中发现了对Ag激发的气道炎症反应的独特模式，其特征在于IL-6、IL-10、IL-17、TGF-β表达增加以及气道中性粒细胞和Treg细胞数量增加。为了将我们在小鼠中的发现应用于人类，我们接下来生成了初步数据，这些数据表明IL-6和嗜中性粒细胞增多的形成对老年受试者哮喘的病理生理学很重要。 因此，我们假设，与年轻的哮喘患者相比，老年哮喘患者将表现出不同的炎症表型，其由IL-6的产生增加指示，这反过来又增加了Th 17细胞的表达以诱导气道嗜中性粒细胞，并且还降低了Treg细胞功能。为了验证我们的假设，我们将收集40名老年（>60岁）和40名年轻成人（21-40岁）哮喘患者（接受标准化低剂量吸入皮质类固醇）和80名年龄匹配的对照组的诱导痰和外周血。然后，我们将：a）与年轻成人哮喘受试者相比，在老年哮喘受试者中建立气道炎性（细胞因子和细胞）表型，并检查与哮喘控制的关联，和B）研究IL-6是否通过增强Th 17表达和降低Treg功能在老年受试者中促成哮喘机制。

项目成果

Effect of aging on sputum inflammation and asthma control.

• DOI: 10.1016/j.jaci.2016.09.015
• 发表时间: 2017-06
• 期刊: The Journal of allergy and clinical immunology
• 作者: Busse PJ;Birmingham JM;Calatroni A;Manzi J;Goryachokovsky A;Fontela G;Federman AD;Wisnivesky JP
• 通讯作者: Wisnivesky JP

The Effect of Age on T-Regulatory Cell Number and Function in Patients With Asthma.

• DOI: 10.4168/aair.2021.13.4.646
• 发表时间: 2021-07
• 期刊: Allergy, asthma & immunology research
• 作者: Birmingham JM;Chesnova B;Wisnivesky JP;Calatroni A;Federman J;Bunyavanich S;Busse PJ
• 通讯作者: Busse PJ