In adult organisms, cells localized primarily in the bone marrow and in low number in other organs have the ability to differentiate into multiple cell phenotypes. One current of repair of injured tissue invokes mobilization and homing of these progenitor cells to sites of injury and their differentiation into organ parenchymal cell types. However, progenitor cells have also been implicated in promoting fibrogenesis by differentiating into lung fibroblasts. Based on our and others studies, we hypothesize that bone marrow derived progenitor cells may promote either lung repair or fibrosis, depending on the nature of the injury and the immune proclivity of the host. In this project we propose to clarify the roles of bone marrow derived stem cells in acute and chronic lung injury. We will conduct studies in a novel rodent model, a genetically modified T-bet deficient mice will be treated chronically with bleomycin to induce progressive pulmonary fibrosis. Therefore, we propose the following hypothesis: 1. In response to a single episode of injury, mesenchymal stem cells contribute to effective repair of the injured lung by modulating the inflammatory response, favoring transient fibrogenesis essential to remodeling and differentiating into lung parenchymal cells. 2. Prolonged or repeated lung injury provokes a maladaptive repair response in which mesenchymal stem cells promote fibrogenesis by favoring a persistent Th2 type immune response and by localizing in the lungs and differentiating into fibroblasts that contribute directly to the fibrosis. 3. A persistent Th2 bias of CD4+ T lymphocytes promotes a maladaptive response to lung injury. Administration of mesenchymal stem cells to Th2 biased animals will exaggerate the fibrotic response to bleomycin . To test these hypothesis, we propose the following specific aims: 1. Using an animal model of progressive pulmonary fibrosis, to compare responses of the lungs to single and multiple intratracheal instillations of bleomycin. 2. To determine effects of mesenchymal stem cell transfer on repeated bleomycin induced lung injury. 3. In vitro and in vivo to determine the role of chemoattractant factors (SDF-1) and Th2 cytokines (IL-4 and IL-13) and TGFf31, in the processes of localization, proliferation and differentiation of bone marrow derived mesenchymal stem cells in the lungs after continues injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01HL084683-04
Application #
7787048
Study Section
Special Emphasis Panel (ZHL1-CSR-H (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2007-04-01
Project End
2011-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$133,413
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Bustos, Martha L; Huleihel, Luai; Kapetanaki, Maria G et al. (2014) Aging mesenchymal stem cells fail to protect because of impaired migration and antiinflammatory response. Am J Respir Crit Care Med 189:787-98
Rojas, Mauricio; Parker, Richard E; Thorn, Natalie et al. (2013) Infusion of freshly isolated autologous bone marrow derived mononuclear cells prevents endotoxin-induced lung injury in an ex-vivo perfused swine model. Stem Cell Res Ther 4:26
Grove, Daniel A; Xu, Jianguo; Joodi, Robert et al. (2011) Attenuation of early airway obstruction by mesenchymal stem cells in a murine model of heterotopic tracheal transplantation. J Heart Lung Transplant 30:341-50
Xu, Jianguo; Gonzalez, Edilson T; Iyer, Smita S et al. (2009) Use of senescence-accelerated mouse model in bleomycin-induced lung injury suggests that bone marrow-derived cells can alter the outcome of lung injury in aged mice. J Gerontol A Biol Sci Med Sci 64:731-9
Iyer, Smita S; Ramirez, Allan M; Ritzenthaler, Jeffrey D et al. (2009) Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis. Am J Physiol Lung Cell Mol Physiol 296:L37-45
Xu, Jianguo; Torres, Edilson; Mora, Ana L et al. (2008) Attenuation of obliterative bronchiolitis by a CXCR4 antagonist in the murine heterotopic tracheal transplant model. J Heart Lung Transplant 27:1302-10