IMPACT OF AGING ON THE DEVELOPMENT OF ASTHMA PHENOTYPES

Asthma is the most common chronic disease of childhood, in which infectious and allergic agents trigger airway inflammation leading to respiratory symptoms. Although generally viewed as a life-long disease, asthma spontaneously remits in some children as they mature for unknown reasons. To examine this phenomenon, we exposed mice of various ages to viral and allergic agents known to induce the key asthma phenotypes of mucus cell metaplasia, airway inflammation, and airway hyperresponsiveness. We found that the induction of asthmatic phenotypes by Sendai virus (SeV) or influenza A virus (IAV) is dependent on juvenile mouse age, while similar changes induced by the allergens ovalbumin and Alternaria alternata are relatively insensitive to age. In response to SeV, juvenile but not older mice exhibited a bias towards type 2 cytokine expression, increased lung infiltration with M2-type macrophages, and a more robust basal cell signature post-challenge. Juvenile mice can be differentiated from mature mice early in acute SeV bronchiolitis in terms of airway mechanics, the distribution of virus-infected cells in the airway, and lung leukocyte composition. We observed qualitative and quantitative changes to alveolar macrophages (AM) with aging, and depletion of these cells before SeV infection widened the age range for the induction of asthma phenotypes into maturity. Our data suggest that evolution of host responses to respiratory viruses may underlie the phenomenon of asthma remission as children mature. They also identify AMs as a mechanistic link between age and the likelihood that viral infection will elicit asthmatic phenotypes.