Grant: Project Grant - Priority Announcement: Acute asthma care across the lifespan

Asthma is a chronic inflammatory disease affecting >300 million people worldwide, and allergic asthma is the most common form. Although most asthmatics are reasonably well controlled by current therapies targeting the inflammatory response, more sophisticated therapies with the ability to reduce the development of asthma and disease exacerbations could impact millions. However, this requires a better understanding of the processes driving these destructive inflammatory responses. We have developed murine models to better understand what happens to the lung after exposure to allergens or respiratory viruses. We focus on two types of models: i) very young mice infected with respiratory syncytial virus (RSV), which in humans is associated with development of wheezing and asthma that can persist into adulthood; and ii) adult mice treated with an inflammatory mediator called IL-33, which in humans is implicated in asthma susceptibility as well as exacerbations. Our data provide evidence that following these exposures, the lung is durably changed, such that inflammation develops to normally innocuous stimuli. These changes are greater in females, in line with the observation that, in humans, more adult females than males have asthma. We have recently linked female sex hormones even in very young mice to these changes. Our goals are to better understand how early-life RSV infection induces long-term changes in the lung linked to asthma susceptibility; how sex hormones in very young mice influence the impact of early-life RSV infection on allergic responses in adults; and how IL-33 durably modifies the lung environment. Our findings will provide insight into mechanisms by which the lung is modified to promote allergic lung inflammation, more so in females, and why these responses are long-lasting. We are hopeful our models will provide information to guide development of novel therapeutic approaches to prevent or treat asthma in all children and all adults.