Airway Cellular and Cytokine Profiles in Older Patients with Asthma

描述(由申请人提供)：对不同哮喘表型的认识已经开始解释儿童和年轻人在疾病严重性、持久性和对治疗的反应方面的差异。新出现的数据表明，老龄化对哮喘也有重要影响；老年哮喘患者的发病率和死亡率更高，可能反映了不同的潜在病理生理和不同的治疗反应。虽然老年哮喘患者的这些变化背后的机制尚未完全确定，但与年龄相关的免疫功能变化可能起到重要作用。为了明确年龄对哮喘、呼吸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建立了一种使用抗原致敏和气道激发的哮喘小鼠模型。老年小鼠对抗原攻击的呼吸道炎症反应具有不同的模式，表现为IL-6、IL-10、IL-17、转化生长因子-β的表达增加，以及大量的中性粒细胞和Treg细胞。为了将我们的小鼠发现转化为人类，我们接下来产生了初步数据，表明IL-6的增强形成和中性粒细胞增多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独特的炎症表型，其指标是IL-6的生成增加，这反过来又增加了Th17细胞的表达，从而诱导气道中性粒细胞减少，并降低了Treg细胞的功能。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)建立老年哮喘患者与年轻成人哮喘患者相比的呼吸道炎症(细胞因子和细胞)表型，并检查与哮喘控制的相关性；b)研究IL-6是否通过增强Th17表达和降低Treg功能在老年人哮喘发病机制中起作用。

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.