Inhalation of crystalline silica in the mining and quarrying industries leads to serious lung inflammation and fibrosis for which there are no therapies. The pathogenic mechanisms of silicosis, as well as other types of lung fibrosis, are poorly understood, but the cytokine TGFB appears key. This is the result of TGFB's effects on pulmonary fibroblasts, particularly its ability to induce extracellular matrix (ECM) production and to drive myofibroblast differentiation. Inhibiting TGFB-mediated pro-fibrotic activities on fibroblasts is thus an attractive therapeutic target. Recently, a receptor/ transcription factor called peroxisome proliferator activated receptor gamma (PPAR() and its natural (15d-PGJ2) and synthetic ligands have emerged as important inhibitors of inflammation. PPARy also has important roles in lipid metabolism. The role of the PPAR( pathway in modulating pulmonary fibrosis is unknown. The overall hypothesis to be tested is that activation of the peroxisome proliferator activated receptor gamma (PPARy) pathway ameliorates pulmonary fibrosis, and that the PPARy pathway can be targeted as a novel therapy for human pulmonary fibrosis. Both natural (15d-PGJ2) and synthetic PPARy agonists (e.g. rosiglitazone, ciglitazone) will be tested for their ability to inhibit key TGFB-mediated fibroblast activation events in vitro (including myofibroblast differentiation and ECM production), and for their ability to inhibit lung fibrosis in vivo. The following 3 specific aims will test the overall hypothesis:
Aim 1. To determine the efficacy of selected PPARy agonists in inhibiting key TGFB-stimulated pro-fibrotic activities in pulmonary fibroblasts.
Aim 2. To determine if PPARy agonists mediate inhibition of key TGFB-induced pro-fibrotic activities in fibroblasts through both PPARy-dependent and independent pathways.
Aim 3. To determine the role of the PPAR( pathway as a modulator of pulmonary fibrosis in vivo, and to determine the efficacy of 15d-PGJ2 and selected PPARy agonists as anti-fibrotics in a silica model of lung fibrosis.
These aims will identify the mechanism of action of PPARy agonists as anti-fibrotics and will generate exciting evidence supporting their utility as novel and efficacious therapies for scarring of the lungs, as well as other organs.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Reynolds, Herbert Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Rochester
Internal Medicine/Medicine
Schools of Dentistry
United States
Zip Code
Conforti, Franco; Davies, Elizabeth R; Calderwood, Claire J et al. (2017) The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis. Oncotarget 8:48737-48754
Kottmann, Robert Matthew; Sharp, Jesse; Owens, Kristina et al. (2015) Second harmonic generation microscopy reveals altered collagen microstructure in usual interstitial pneumonia versus healthy lung. Respir Res 16:61
Jones, Kyle M; Randtke, Edward A; Howison, Christine M et al. (2015) Measuring extracellular pH in a lung fibrosis model with acidoCEST MRI. Mol Imaging Biol 17:177-84
Guo, Jia; Yao, Hongwei; Lin, Xin et al. (2015) IL-13 induces YY1 through the AKT pathway in lung fibroblasts. PLoS One 10:e0119039
Olsen, Keith C; Epa, Amali P; Kulkarni, Ajit A et al. (2014) Inhibition of transglutaminase 2, a novel target for pulmonary fibrosis, by two small electrophilic molecules. Am J Respir Cell Mol Biol 50:737-47
Jeon, Kye-Im; Kulkarni, Ajit; Woeller, Collynn F et al. (2014) Inhibitory effects of PPAR? ligands on TGF-?1-induced corneal myofibroblast transformation. Am J Pathol 184:1429-45
Kulkarni, Ajit A; Thatcher, Thomas H; Hsiao, Hsi-Min et al. (2013) The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis. PLoS One 8:e63798
Huxlin, Krystel R; Hindman, Holly B; Jeon, Kye-Im et al. (2013) Topical rosiglitazone is an effective anti-scarring agent in the cornea. PLoS One 8:e70785
Kuriyan, A E; Lehmann, G M; Kulkarni, A A et al. (2012) Electrophilic PPAR? ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring. Exp Eye Res 94:136-45
Kottmann, Robert Matthew; Kulkarni, Ajit A; Smolnycki, Katie A et al. (2012) Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-?. Am J Respir Crit Care Med 186:740-51

Showing the most recent 10 out of 42 publications