A number of pharmacologic or genetic interventions have been shown to prevent the development of fibrosis following the intratracheal administration of bleomycin, a commonly used model for the study of lung fibrosis. These studies have provided important mechanistic insights into the development of pulmonary fibrosis and have identified both transforming growth factor-beta (TGF-2) and peroxsome prolifeator- activated receptor-gamma (PPAR3) as important mediators of fibrosis. In our preliminary data, we observed that the administration of a proteasome inhibitor to mice 8 days after the administration of bleomycin resulted in marked attenuation of lung fibrosis. Similar protection was observed in a bleomycin induced skin fibrosis model of scleroderma. Additional preliminary data suggest that proteasomal inhibition results in increased abundance and activity of PPAR3, which functions as an inhibitor of TGF-2. We hypothesize that the administration of proteasomal inhibitors prevents the ubiquitin-mediated degradation of PPAR-3 in normal human lung fibroblasts and in the mouse lung thereby inhibiting the transcriptional response to active TGF-2 and attenuating fibrosis. We have generated three interrelated specific aims to identify the molecular mechanisms by which PPAR3 is degraded and by which this degradation is accelerated in the presence of TGF-2.
Aim 1. Is PPAR-3 required for inhibition of the transcriptional response to active TGF-2 induced by proteasomal inhibition in normal human lung fibroblasts? Aim 2. How is PPAR-3 targeted for proteasomal degradation in normal human lung fibroblasts? Aim 3. Does the bortezomib- mediated increase in the protein abundance of PPAR3 prevent the development of lung fibrosis in mice treated with bleomycin downstream of the activation of TGF- 21? This application represents a highly innovative effort that employs molecular tools in cell culture systems and sophisticated mouse models to elucidate the mechanisms by which proteasomal inhibition might prevent the development of pulmonary fibrosis. Our preliminary data support the feasibility of the proposed experiments and provide support for our focus on the ubiquitin-proteasomal system's regulation of PPAR3.
Many lung diseases including the Acute Respiratory Distress Syndrome, Idiopathic Pulmonary Fibrosis, Sarcoidosis, Scleroderma and a variety of others cause scarring (fibrosis) of the lung that if progressive can result in respiratory failure or death. In this proposal, the investigators have found that the administration of an FDA approved medication used to treat some cancers, bortezomib, is effective at preventing the development of lung and skin fibrosis in mice. They propose a series of experiments to determine how this medication protects against fibrosis. Early data from these experiments suggest that bortezomib increases the concentration of a key protein involved in the development of fibrosis. Targeting this protein would represent a new and novel therapeutic strategy for the treatment of Veterans with lung fibrosis.
| Sala, Marc A; Balderas-Martínez, Yalbi Itzel; Buendía-Roldan, Ivette et al. (2018) Inflammatory pathways are upregulated in the nasal epithelium in patients with idiopathic pulmonary fibrosis. Respir Res 19:233 |
| Kim, Seok-Jo; Cheresh, Paul; Eren, Mesut et al. (2017) Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis. Am J Physiol Lung Cell Mol Physiol 313:L16-L26 |
| Gonzalez-Gonzalez, Francisco J; Chandel, Navdeep S; Jain, Manu et al. (2017) Reactive oxygen species as signaling molecules in the development of lung fibrosis. Transl Res 190:61-68 |
| Jablonski, Renea P; Kim, Seok-Jo; Cheresh, Paul et al. (2017) SIRT3 deficiency promotes lung fibrosis by augmenting alveolar epithelial cell mitochondrial DNA damage and apoptosis. FASEB J 31:2520-2532 |
| Fernandez, Ramiro; Chi, Monica; Ison, Michael G et al. (2017) Sequelae of Donor-derived Mollicutes Transmission in Lung Recipients. Am J Respir Crit Care Med 195:687-689 |
| Sennello, Joseph A; Misharin, Alexander V; Flozak, Annette S et al. (2017) Lrp5/?-Catenin Signaling Controls Lung Macrophage Differentiation and Inhibits Resolution of Fibrosis. Am J Respir Cell Mol Biol 56:191-201 |
| Misharin, Alexander V; Morales-Nebreda, Luisa; Reyfman, Paul A et al. (2017) Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 214:2387-2404 |
| Bharat, Ankit; Chiu, Stephen; Zheng, Zhikun et al. (2016) Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation. Am J Respir Cell Mol Biol 55:532-541 |
| Bhattacharyya, Swati; Wang, Wenxia; Morales-Nebreda, Luisa et al. (2016) Tenascin-C drives persistence of organ fibrosis. Nat Commun 7:11703 |
| Peteranderl, Christin; Morales-Nebreda, Luisa; Selvakumar, Balachandar et al. (2016) Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. J Clin Invest 126:1566-80 |
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