Fibrotic lung diseases, including idiopathic pulmonary fibrosis, represent a heterogeneous group of diseases in which progressive parenchymal fibrosis disrupts the structure and gas exchanging functions of the lungs. In the microenvironment of the distal lung, this pathobiology is characterized by an increased population of fibroblasts and augmented collagen and matrix synthesis. In addition to fibroblasts, recent evidence points to a critical role for lung epithelial cells in determining the extent and progression of lung fibrosis. The importance of epithelial cells in fibrogenesis is highlighted by the identification of mutations in the epithelial-restricted gene encoding surfactant protein C (SP-C), that are associated with familial pulmonary fibrosis. While a variety of pathways have been implicated in cross-talk between epithelium and fibroblasts, the critical mechanisms by which epithelial cells influence the effector fibroblast population are not well established. We hypothesize that interactions between lung epithelial cells and fibroblasts determine the severity and progression of lung fibrosis. Specifically, we propose that: 1) epithelial cells, predominantly alveolar type II epithelium, contribute to fibrosis by undergoing epithelial-mesenchymal transition in vivo, 2) epithelial cells regulate proliferation and survival of resident fibroblasts, and 3) phenotypic changes in alveolar type II epithelial cells that cause endoplasmic reticulum stress lead to lung fibrosis by impairing re-epithelialization and inducing an increased population of effector fibroblasts following injury.
Three specific aims are proposed to investigate this hypothesis: 1) to define the extent of epithelial-mesenchymal transition as a source of fibroblasts in experimental pulmonary fibrosis, 2) to determine the pro-fibrotic effects of mutant SP-C expression in alveolar type II epithelial cells, and 3) to investigate the effects of epithelial dysfunction induced by expression of mutant SP-C on fibroblast recruitment/activation and development of lung fibrosis. These studies will use transgenic mice and cell culture systems to define essential roles for epithelial cells in the generation of lung fibrosis. Identifying the impact of alveolar type II epithelial cell phenotype on induction and maintenance of specific populations of effector fibroblasts will provide new insights into the pathogenesis of lung fibrosis and identify new treatment approaches. Relevance to public health: Progressive fibrotic lung diseases frequently lead to respiratory failure and death. These studies will provide a better understanding of the basic mechanisms of disease pathogenesis and suggest new treatment approaches for these devastating diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085317-04
Application #
7787096
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
2007-04-10
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$383,750
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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