This grant application seeks to investigate the biological role(s) of the inflammatory molecule, IL-17 (interleukin-17), in the induction of epithelial-mesenchymal transition (EMT). EMT, the conversion of epithelial cells into spindle-shaped fibroblasts, has been increasingly recognized in wound healing and fibrogenesis in fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and lung transplant associated obliterative bronchiolitis (OB). IPF is a fatal disease with progressive scarring of the lung tissue with no known causes or effective therapies. Although lung transplantation is the only definitive therapy for many end stage pulmonary diseases including IPF, chronic rejection (OB) sets in resulting in 50% five-year survival rate for lung transplant recipients - the worst of all solid organ transplant recipients. Recent studies demonstrate inflammatory surroundings and dysregulated epithelial repair as a key event responsible for fibrotic diseases such as IPF and OB. It has been observed that type V collagen [col (V)], an autoantigen, has a key role in IPF and this col (V) autoimmunity correlates with localized IL-17 gene expression. A recent study published in Journal of Experimental Medicine has shown an additive fibrotic effect of IL-1? and IL-17. We have observed that neutralizing IL-17A/F protects lungs from developing fibrosis. EMT may be a potential mechanism contributing towards fibrosis and the current proposal offers the excitement for the possibility of discovering IL-17 as a novel promoter of EMT, and a plausible link between inflammation and fibrosis. Our preliminary studies provide a strong rationale for the hypothesis that IL-17 induces EMT in airway epithelial cells. Specifically, we propose: (1) To determine the role of IL-17A or IL-17F or both in the induction of EMT in airway epithelial cells. (2) To determine specific enzymes that trigger and control this event mediated by IL-17A or IL-17F or both. (3) To determine the role of IL-17A or IL-17F or both in the induction of EMT in two experimental mouse models. We will also use mice with fluorescent protein tagged to specific airway cell types and determine their fate in a fibrotic lung. The results of this research promise the identification of a novel biomarker for patients with predisposition to IPF and OB and to demonstrate the feasibility of developing novel treatment strategies for IPF and OB.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with scarring of the lungs with lung transplantation as the only known therapy. However, chronic lung rejection (obliterative bronchiolitis-OB) sets in and the transplant patients have a 50% five-year survival rate. The objective of this application is directly relevant to the mission of the National Heart, Lung and Blood Institute, by proposing the identification of interleukin-17-specific therapeutic targets to block the conversion of airway epithelial cells to scar forming cells by a process called epithelial to mesenchymal transition (EMT).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL109288-03
Application #
8501670
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2011-08-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$371,280
Indirect Cost
$133,280
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Gu, Hongmei; Mickler, Elizabeth A; Cummings, Oscar W et al. (2014) Crosstalk between TGF-?1 and complement activation augments epithelial injury in pulmonary fibrosis. FASEB J 28:4223-34
Suzuki, Hidemi; Lasbury, Mark E; Fan, Lin et al. (2013) Role of complement activation in obliterative bronchiolitis post-lung transplantation. J Immunol 191:4431-9
Vittal, Ragini; Fisher, Amanda; Gu, Hongmei et al. (2013) Peptide-mediated inhibition of mitogen-activated protein kinase-activated protein kinase-2 ameliorates bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 49:47-57
Vittal, Ragini; Fan, Lin; Greenspan, Daniel S et al. (2013) IL-17 induces type V collagen overexpression and EMT via TGF-ýý-dependent pathways in obliterative bronchiolitis. Am J Physiol Lung Cell Mol Physiol 304:L401-14