The goal of this application is to define the role of different cell types, particularly lung epithelial cells, in the development pulmonary fibrosis. Progressive fibrosis is a common feature of many chronic diseases leading to significant morbidity and death. Fibrosis can also occur without any known cause in diseases such as Idiopathic Pulmonary Fibrosis (IPF). IPF is a devastating disease that affects greater than 5 million people world-wide. The median survival is 3-5 years from time of diagnosis and current medical therapy is largely ineffective. Despite intense investigation, we still have a poor understanding into the mechanisms that regulate fibrosis and even fundamental questions such as which cells produce the collagen-rich scar remain unanswered. Prior work has focused mainly on the function of fibroblasts. However, a new paradigm is emerging in which the function of epithelial cells plays a critical role in determining the progression of fibrogenesis. This possibility is exciting because the role of epithelial cells is undefined and a clearer understanding of the mechanisms that regulate epithelial cell behavior has the potential of offering new targets for better therapeutic intervention. We have developed several techniques in the last few years to define the function and regulation of lung epithelial cells during fibrogenesis. Using animal models, we and others have found that during fibrogenesis, epithelial cells are capable of transitioning into fibroblast-like cells in a process of epithelial-mesenchyma transition (EMT). During EMT, lung epithelial cells may acquire the ability to produce type I collagen which is the major component of the fibrotic scar. The extent to which lung epithelial cells or any other cell type contributes to the collagen-rich fibrosis remains unknown and we have generated a mouse in which we can delete the type I collagen gene in different cell types. Thus, we will be able to definitively determine which cell type(s) contribute directly to collagen synthesis during fibrogenesis. Lung epithelial cell EMT may also be important for recruiting other collagen-producing cells. We have developed a system to study lung epithelial cells in culture and determine if they release signaling molecules that can attract and activate other cells types potentially involved in fibrogenesis. In this way, lung epithelial cells may be critica in orchestrating the fibrotic process. Finally, we will study a family of transcription factors, the Helix- Loop-Helix (HLH) family that has been implicated in regulating EMT. Using combined animal model and cell culture approach we will be able to determine if these HLH factors regulate the ability of epithelial cells to produce collagen, signal to other cell types and regulae fibrosis. These studies will help define previously unexplored mechanisms that may regulate fibrosis with the potential of designing new and better therapies.

Public Health Relevance

Despite years of research, pulmonary fibrosis remains a devastating problem without good therapy. The function of epithelial cells during fibrosis remains poorly characterized but emerging evidence suggests that they have a critical role. With greater understanding into the relatively unexplored function of epithelial cells, a new paradigm for the progression of fibrosis may emerge with the potential for novel therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL108904-01A1
Application #
8290684
Study Section
Special Emphasis Panel (ZRG1-CVRS-G (02))
Program Officer
Eu, Jerry Pc
Project Start
2012-05-15
Project End
2017-03-31
Budget Start
2012-05-15
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$388,750
Indirect Cost
$138,750
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kleaveland, Kathryn R; Moore, Bethany B; Kim, Kevin K (2014) Paracrine functions of fibrocytes to promote lung fibrosis. Expert Rev Respir Med 8:163-72
Yang, Jibing; Velikoff, Miranda; Canalis, Ernesto et al. (2014) Activated alveolar epithelial cells initiate fibrosis through autocrine and paracrine secretion of connective tissue growth factor. Am J Physiol Lung Cell Mol Physiol 306:L786-96
Kleaveland, Kathryn R; Velikoff, Miranda; Yang, Jibing et al. (2014) Fibrocytes are not an essential source of type I collagen during lung fibrosis. J Immunol 193:5229-39
Yang, Jibing; Wheeler, Sarah E; Velikoff, Miranda et al. (2013) Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins. Am J Pathol 183:1559-70