Grant: Project Grant

Although Influenza is a common seasonal respiratory infection that is cleared by 7-10 days in most healthy individuals, there are some, particularly the elderly and the very young, that are severely affected. This involves excessive lung inflammation that may lead to major problems in lung function, lack of proper Oxygen transfer to the body, and death. Influenza-related deaths in Canada average 7000/year, a majority of which are people 65 years or older. Severity is associated with "leakiness" of the lung lining (composed of epithelial cells) which normally helps keep external infections and particles out of the bloodstream. Abnormal function of epithelial cells leads to excessive fluid and cells in the lung spaces and subsequent poor lung function. Therapies thus far tested have limited success in these severe cases. Hormone-like molecules called cytokines are elevated in severe acute lung infections and promote lung inflammation and changes in epithelial cells and barrier dysfunction. In this proposal, we investigate the role of one of these cytokines called Oncostatin M. We have recently discovered Oncostatin M is higher in mouse lungs infected with Influenza, and excitingly, that inhibiting this cytokine pathway in mice markedly decreases the lung inflammation and dysfunction. We believe OSM has prominent role in predisposing humans to severe disease, which is greater in adult female patients than males. We need to investigate the effect of biological sex and age on roles of OSM in preclinical systems. We propose to study how Oncostatin M gets stimulated in mouse models of lung inflammation due to Influenza infection, how Oncostatin M regulates epithelial cell function, and whether various ways of inhibiting the Oncostatin M pathway can suppress this process in our mouse models. This may lead to a new approach to treat patients with severe lung inflammation to decrease morbidity and mortality.