Grant: Project Grant

Buildup of scar tissue in chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) results in local events in lungs that compromise lung function. These include the accumulation of inflammatory cells and decreases in oxygen exchange, and IPF patients have an average survival time of 3 years after diagnosis. Although multiple molecules may collectively determine the severity of disease, we believe that certain hormone-like molecules termed cytokines play a crucial role in the development of this lung pathology. Our novel proposal hypothesizes that one of these cytokines in particular, a gp130 cytokine family member Oncostatin M (OSM), is up-regulated in lung fibrosis and interacts with cells to induce a partnering cytokine called IL-33. These two molecules can orchestrate a variety of inflammatory functions that cause progression to severe and chronic fibrosis. We will test specifically how these two cytokines regulate actions of both mouse and human lung cells in tissue culture, test for ways to inhibit their function, and use mice that are deficient in the IL-33 gene to determine if our hypothesis holds true in mice. We will also determine the spectrum of genes that are increased in severe fibrosis of our established animal models involving OSM and IL-33, and correlate with the spectrum of genes we can detect that are regulated in human IPF samples of stored lung biopsied tissue. We predict that these studies will demonstrate the importance of OSM and IL-33, and the gene signatures they induce, in models of severe respiratory disease in order to define a framework for new approaches in treatments for lung fibrosis.