Grant: Project Grant

Lung fibrosis occurs when scar tissue forms within the lungs, making it difficult to breathe. Fibrosis gets worse over time, and there is no cure. The only treatment is a lung transplant, but ~50% of people who need transplants do not get them. Most of the >5M people worldwide with lung fibrosis, including 14,000 people in Canada each year, live for only 3-5 years after their diagnosis. A cure could save their lives. Fibrosis is the outcome of chronic healing of repeated microinjuries to delicate lung tissues. Rather than repairing injuries and stopping, fibroblasts continue to replace normal with scar tissue. Fibroblasts make scar tissue when they encounter the active form of TGF-ß1. In later-stage fibrosis, we showed that fibroblasts continue to produce scar tissue by activating TGF-ß1 stored in the scar matrix. But how do they start forming scar tissue when matrix reservoirs of TGF-ß1 do not yet exist? We propose that other cells store TGF-ß1 in sites that become accessible only after repeated injury, thereby activating fibroblasts in areas that are not yet scarred. Stopping fibroblasts from encountering active TGF-ß1 in these sites can mitigate fibrosis. Our results show that normal lungs store TGF-ß1 in endothelial cells lining alveolar blood vessels and in alveolar macrophages. This project will investigate whether these stores are the source of the TGF-ß1 that fibroblasts encounter and activate in newly injured sites. We will determine the molecular details by which TGF-ß1 on macrophages and endothelial cells becomes accessible to fibroblasts and is activated at sites of lung injury. Our experiments will use human cell cultures, preclinical mouse models, and human lung tissues. Our results will demonstrate that TGF-ß1 sourced from endothelial cells and alveolar macrophages triggers fibroblasts to initiate repair, and will delineate the molecular pathways involved. We anticipate that these pathways can be targeted to develop new drugs for lung fibrosis.