Grant: Project Grant

Both the incidence and severity of asthma have been increasing steadily over the last 2-3 decades. Although asthma in childhood is more prominent in boys, this sex difference changes around the time of puberty, when asthma prevalence declines in men and rises in women. We have developed a model of allergic lung inflammation where we deliver (directly to the lungs) a cytokine called IL-33, which is implicated in asthma onset. Our data show that adult mice treated with this cytokine develop 'acute' inflammation in the lung within days that is similar in many aspects to the inflammation found in asthmatics with established disease. We have found that females have much greater responses than males. We have also developed a combined viral infection-asthma model that mimics studies showing that, in children, there is an association between some viral infections, including respiratory syncytial virus (RSV) and asthma development. RSV infection increases IL-33 levels in the lung, particularly in young mice, and thus we believe responses in the lung driven by RSV infection are similar to those caused by IL-33. As part of our ongoing studies, we are characterizing an inhibitor we developed called STAT6-IP. Our data show that STAT6-IP reduces some of the inflammatory responses in the lung caused by IL-33 delivery in adults or RSV infection in young mice. Our goals are now to define which responses promote asthma onset, including disease that develops as a consequence of prior RSV infection. We will define how these responses differ in males and females and we will define how they are modulated by STAT6-IP, recognizing that STAT6-IP may provide protection by targeting different responses in males and females. We believe these preclinical studies may provide a foundation to reduce the induction of asthma in both men and women.