Idiopathic pulmonary fibrosis (IPF) remains a devastating fibrotic parenchymal lung disease with high morbidity and mortality, for which there are no effective therapies. Consequently, it becomes increasingly important to identify molecular pathways that are targetable for therapeutic intervention. This proposal seeks to address this unmet need by investigating the role of TNF- in the resolution of pulmonary fibrosis using the well- characterized bleomycin model in mice. In preliminary studies we have shown that the intratracheal administration of TNF- at the peak of the bleomycin-induced fibrotic response accelerates resolution and that mice with a genetic TNF- deficiency have impaired resolution of fibrosis. These and other considerations have led us to hypothesize that TNF- plays an integral role in the resolution of pulmonary fibrosis through effects on macrophages and myofibroblasts. We hypothesize that TNF- alters the phenotype of both of these cell populations reducing their pro-fibrogenic phenotype and allowing them to aid in the resolution process.
Specific aim 1 will address the hypothesis that TNF- induces a switch in macrophage programming from alternative to classical, reducing the production of pro-fibrotic mediators including TGF- and IGF-I, increasing pro-inflammatory cytokine production (TNF-) and enhancing matrix metalloproteinase production to initiate tissue remodeling and the restoration of normal pulmonary architecture. The goal of specific aim 2 is to address the hypothesis that TNF- promotes myofibroblast apoptosis in a two-step process, first by directing myofibroblasts de-differentiation to fibroblasts, and second by sensitizing these fibroblasts to undergo Fas- mediated apoptosis. Finally, specific aim 3 will translate our work into human disease using IPF-derived myofibroblasts and a humanized mouse model of fibrosis. Our proposed studies represent the first time TNF- has been investigated as a key player in the resolution process of pulmonary fibrosis. It also represents a novel opportunity to identify new therapeutic targets for the treatment of IPF. Thus, a long-term goal of this proposal is to translate our anticipated findings into the development of therapies for patients diagnosed with fibrotic lung diseases, including IPF.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is a fatal condition that leads to scarring of the lungs. The incidence of IPF increases with age and is more common in males compared to females. Little is known about the development of IPF in humans, but cigarette smoking and environmental dust exposure, both common among US veterans, constitute two established risk factors for disease development. In addition, recently deployed military persons exposed to burn pits and pollutants may also have an increased risk of IPF as they age. Thus, patients in the VA health care system are expected to have a higher rate of IPF than the general population, establishing a major potential health issue facing US veterans. The Department of Veterans Affairs has recently acknowledged this serious risk to US veterans and is currently enrolling patients for the Rehabilitation of IPF Patients clinical trial. Our proposed studies represent a novel opportunity to identify new therapeutic targets for the treatment of IPF and other fibrotic lung diseases.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2BX002401-04
Application #
9525081
Study Section
Respiration (PULM)
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2018-04-01
Budget End
2019-03-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA Eastern Colorado Health Care System
Department
Type
DUNS #
003252830
City
Denver
State
CO
Country
United States
Zip Code
80220