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.
In this application we aim to establish the airway inflammatory (cytokine and cellular) phenotypes in older (>60 years) asthmatic subjects in comparison to younger adult asthma subjects (21 to 40 years old) and examine association with asthma control. We will examine whether the cytokine IL-6 contributes to the mechanisms of asthma in the older subjects by enhancing Th17 expression and decreasing Treg function. Our project will serve as an initial step to our overall goal to establish the mechanisms by which age modulates inflammation and hence the asthma phenotype, and from this information, develop new and more effective treatments for this at risk group.
|Busse, Paula J; Birmingham, Janette M; Calatroni, Agustin et al. (2017) Effect of aging on sputum inflammation and asthma control. J Allergy Clin Immunol 139:1808-1818.e6|