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-b) and peroxsome prolifeator-activated receptor- gamma (PPAR-g) as important mediators of fibrosis. we have shown that preventing the degradation of PPAR- g in response to TGF- impairs the expression of collagen and other profibrotic genes in normal human lung fibroblasts, lung fibroblasts from patients with pulmonary fibrosis, skin fibroblasts from patients with scleroderma and mice treated with bleomycin. In addition, we have generated preliminary data suggesting that TGF-b induces mitochondrial reactive oxygen species (ROS), which contribute to the degradation of PPAR-g and are required for a full TGF-b transcriptional response. We hypothesize that TGF-b-induced mitochondrial ROS via Smad3 activation through the ALK5 receptor. These mitochondrially derived ROS activate downstream kinases and induce the degradation of PPAR-g to amplify the expression of TGF-b dependent genes. We propose to test these hypotheses in a series of experiments in vitro, in animal models of acute lung injury/fibrosis and with alveolar fluid from patients with pulmonary fibrosis and ARDS.
Aim -1: To determine the mechanism by which TGF- induces the generation of mitochondrial ROS.
Aim -2: To determine the mechanism by which mitochondrial ROS modulate TGF--induced gene transcription.
Aim -3: To determine whether fibroblast specific mitochondrial ROS are required for the development of lung fibrosis in murine models and the importance of mitochondrial ROS in TGF--mediated gene expression in patients with lung fibrosis. 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 mitochondrial ROS regulate the development of pulmonary fibrosis. Our preliminary data support the feasibility of the proposed experiments and provide support for our focus on the TGF-b mediated regulation of PPAR-g via induction of mitochondrial ROS. The composition of our research group and all of the proposed experiments are designed to identify novel therapeutic targets for the treatment of lung fibrosis.
Impaired lung healing can lead to lung fibrosis or scarring of the lung and is a devastating disease with no proven treatment. These experiments are designed to identify new treatments to help Veteran's at risk for or suffering from abnormal lung healing.
| 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 |
Showing the most recent 10 out of 35 publications
