Idiopathic pulmonary fibrosis (IPF/UIP) is a fibrosing interstitial lung disease characterized by the accumulation and persistence of myofibroblasts in the lung parenchyma. While much has been learned about the origin of myofibroblasts in pulmonary fibrosis, little is known about the mechanism(s) that promote their persistence. Recent studies in human IPF/UIP patients and in animal models of this disease have suggested that: (i) fibrosis can progress in the absence of a robust inflammatory response, and (ii) fibrosis and sub-pleural honeycombing are worsened in the absence of the pro-inflammatory cytokine, TNF-a. These findings raise two fundamental questions: 1) Can alterations in pulmonary TNF-a expression be exploited to resolve pulmonary fibrosis? 2) Are macrophages, a key cell type implicated in TNF-a production in the lung, involved in the resolution of fibrosis via the production of TNF-a? The overall goal of this F32 application is to investigate these questions. It is hypothesized that (i) myofibroblast apoptosis requires a conditional sequence of signals initiated by macrophage-derived TNF-a, and (ii) restoration of TNF-a production during fibrosis will resolve the fibrotic response. The central hypotheses will be addressed by two specific aims. The goal of aim one is to investigate the potential role of macrophages in the endogenous production of TNF-a during the resolution of pulmonary fibrosis. The goal of aim one is to investigate the role of TNF-a in promoting the resolution of pulmonary fibrosis. Relevance to Public Health Fifty percent of patients with biopsy proven IPF/UIP die within three years of diagnosis and there is no known effective therapy. The proposed studies are expected to provide novel insights into the relationship between lung inflammation and fibrosis and how these events may be manipulated to slow or reverse the relentless progression of this usually fatal disorder.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-F10-S (21))
Program Officer
Colombini-Hatch, Sandra
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Redente, Elizabeth F; Keith, Rebecca C; Janssen, William et al. (2014) Tumor necrosis factor-? accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am J Respir Cell Mol Biol 50:825-37
Keith, Rebecca C; Sokolove, Jeremy; Edelman, Benjamin L et al. (2013) Testosterone is protective in the sexually dimorphic development of arthritis and lung disease in SKG mice. Arthritis Rheum 65:1487-93
Wynes, Murry W; Edelman, Benjamin L; Kostyk, Amanda G et al. (2011) Increased cell surface Fas expression is necessary and sufficient to sensitize lung fibroblasts to Fas ligation-induced apoptosis: implications for fibroblast accumulation in idiopathic pulmonary fibrosis. J Immunol 187:527-37
Redente, Elizabeth F; Jacobsen, Kristen M; Solomon, Joshua J et al. (2011) Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol 301:L510-8
Graham, Brian B; Mentink-Kane, Margaret M; El-Haddad, Hazim et al. (2010) Schistosomiasis-induced experimental pulmonary hypertension: role of interleukin-13 signaling. Am J Pathol 177:1549-61