Idiopathic pulmonary fibrosis (IPF) accounts for more than half of the cases of interstitial lung disease. Patients suffering from IPF develop a progressive loss of lung function and die, on average, 3 years after diagnosis. In addition to fibrosis, alveolar type II cells are abnormal in IPF lungs. However, their role in disease pathogenesis remains undefined. This proposal examines the novel hypothesis that epithelial cells directly participate in the formation of lung fibrosis by transitioning into collagen secreting mesenchymal cells. Within IPF lung there is a subpopulation of epithelial cells predisposed to transition into fibroblasts. These epithelial derived fibroblasts are a major source of the matrix remodeling and fibrosis that occurs in IPF lung.
Specific aims pursued to address this hypothesis are: 1) To establish the unique phenotypic characteristics of alveolar type II cells purified from lungs of IPF patients. 2) To isolate and characterize an alveolar Type II cell subtype expressing CD15 found in IPF lungs. Approach: To pursue these aims, pure populations of Type II cells will be isolated from normal and IPF lungs using FACS sorting for E-cadherin. Gene expression arrays, rt-PCR, and immunohistochemistry will be used to define changes in gene expression unique to IPF Type II cells that may contribute to disease pathogenesis. The role of candidate genes that promote epithelial to mesenchymal transition (EMT) of IPF Type II cells will be confirmed in an in vitro assay of EMT.
In Aim 2, FACS sorting will be used to isolate a Type II cell subtype expressing the cell surface marker CD15. This subtype represents up to 6% of Type II cells in IPF lungs. Purified isolates of CD15+ type cells will be compared to CD15- Type II cells for their ability to proliferate, undergo apoptosis, or transition to mesenchymal cells. Gene expression arrays will be used to define their unique genetic phenotype and how it relates to the pathogenesis of IPF. Significance: By completing the proposed aims, significant gaps in knowledge of the pathogenesis of IPF and basic lung biology will be resolved including;1) The studies will provide new data that specifically phenotype differences between normal and fibrotic Type II cells. 2) They will establish that EMT occurs in IPF lungs and the mediators of this process, 3) They will establish for the first time a specific Type II cell subtype that exists within human lung and the distinct phenotypic characteristics of this phenotype, 4) In addition to advancing our understanding of the pathogenesis of lung fibrosis, the new data and technologies developed via these experiments can be used in future studies of the pathogenesis of IPF and the biology of alveolar Type II cells in human lung.

Public Health Relevance

Idiopathic pulmonary fibrosis, the most common form of lung fibrosis, is a deadly disease with average survival of three years. This proposal applies novel technologies to purify and characterize alveolar Type II cells and Type II cell subtypes (CD15+) from the lungs of patients with idiopathic pulmonary fibrosis. Following purification, the unique biological characteristics of IPF Type II cells and CD15+ Type II cells will be established. By broadly analyzing the unique biology of IPF Type II cells, these studies have the potential to identify unsuspected causes of Idiopathic pulmonary fibrosis and could lead to the development of new therapies that favorably modulate outcomes of this devastating disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Grants (R21)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Eu, Jerry Pc
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Wolters, Paul J; Collard, Harold R; Jones, Kirk D (2014) Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol 9:157-79
Cha, Seung-Ick; Ryerson, Christopher J; Lee, Joyce S et al. (2012) Cleaved cytokeratin-18 is a mechanistically informative biomarker in idiopathic pulmonary fibrosis. Respir Res 13:105
Cha, Seung-Ick; Chang, Christine S; Kim, Eun Kyung et al. (2012) Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis. Histopathology 61:98-106
Marmai, Cecilia; Sutherland, Rachel E; Kim, Kevin K et al. (2011) Alveolar epithelial cells express mesenchymal proteins in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 301:L71-8