Abstract

High dose chemoradiotherapy is used to treat patients with malignancies undergoing BMT. The most common regimen remains high dose Cytoxan (Cy) and total body irradiation (TBI) which has lung i injury (termed idiopathic pneumonia syndrome: IPS) as a major complication. Mortality is at least 75%.We have established murine models using Cy/TBI and alIoBMT. Alveolar type 2 (AT2) cells are responsible for surfactant secretion and fluid and solute clearance. Our central hypothesis is that strategies that preserve, speed regeneration of, or replace AT2 cells will have a major impact on lung repair post-BMT. Cytokines have been shown to regulate the development and proliferation of epithelial cells. Fibroblast growth factor-7 (fgf-7), also known as keratinocyte growth factor (KGF), binds to its receptor, FgfR2-111b, expressed on AT2 cells. Fgf-7 protects AT2 cells from injury induced. Based on the model that AT2 are targets for IPS injury, we hypothesized that fgf-7 pretreatment would prevent AT2 damage or hasten AT2 cell repair after BMT, reducing IPS injury. Our data indicate fgf-7 effects are associated with a reduced frequency of injured AT2 cells.
In aim 1, we will determine the efficacy of and mechanism(s) responsible for the effects of fgf-7 on preventing or treating IPS, focusing upon AT2 cells.
In aim 2, we will determine whether cellular therapies can be used to prevent or treat IPS injury. We hypothesize that marrow stromal cells (MSCs), also known as mesenchymal stem cells, or multipotent adult progenitor cells (MAPCs) or AT2 cells differentiated from these progenitor cells will result in alveolar re-epithelialization when used alone or along with fgf-7. Since both MSCs and MAPCs have been shown to have the capacity to differentiate into pulmonary epithelial cells, the peri-BMT administration of undifferentiated or AT2 differentiated MSCs and MAPCs offer promise for aiding in lung repair post-BMT. These translatable approaches offer new avenues for the prevention and treatment of IPS.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL055209-10
Application #
6864004
Study Section
Special Emphasis Panel (ZRG1-ONC-J (03))
Program Officer
Peavy, Hannah H
Project Start
1995-09-15
Project End
2010-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
10
Fiscal Year
2005
Total Cost
$373,750
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Raza, Kashif; Larsen, Trevor; Samaratunga, Nath et al. (2014) MSC therapy attenuates obliterative bronchiolitis after murine bone marrow transplant. PLoS One 9:e109034
Wendt, Christine; Tram, Kevin; Price, Andrew et al. (2013) Club cell secretory protein improves survival in a murine obliterative bronchiolitis model. Am J Physiol Lung Cell Mol Physiol 305:L642-50
Blazar, Bruce; White, Eric S; Couriel, Daniel (2012) Understanding chronic GVHD from different angles. Biol Blood Marrow Transplant 18:S184-8
Yi, Dandan; Wiedmann, Timothy Scott; Naqwi, Amir et al. (2012) Distribution of aerosols in murine obliterative bronchiolitis lungs by fluorescent imaging. Exp Lung Res 38:325-32
England, Kristen A; Price, Andrew P; Tram, Kevin V et al. (2011) Evidence for early fibrosis and increased airway resistance in bone marrow transplant recipient mice deficient in MMP12. Am J Physiol Lung Cell Mol Physiol 301:L519-26
Kelly, Ryan M; Goren, Emily M; Taylor, Patricia A et al. (2010) Short-term inhibition of p53 combined with keratinocyte growth factor improves thymic epithelial cell recovery and enhances T-cell reconstitution after murine bone marrow transplantation. Blood 115:1088-97
Price, Andrew P; England, Kristen A; Matson, Amy M et al. (2010) Development of a decellularized lung bioreactor system for bioengineering the lung: the matrix reloaded. Tissue Eng Part A 16:2581-91
Gram, Kendra; Yang, Shuxia; Steiner, Marie et al. (2009) Simultaneous absence of surfactant proteins A and D increases lung inflammation and injury after allogeneic HSCT in mice. Am J Physiol Lung Cell Mol Physiol 296:L167-75
Kelly, Ryan M; Highfill, Steven L; Panoskaltsis-Mortari, Angela et al. (2008) Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation. Blood 111:5734-44
Guimond, Martin; Leonard, Warren J; Spolski, Rosanne et al. (2008) Thymic stromal lymphopoietin is not necessary or sufficient to mediate the thymopoietic effects of keratinocyte growth factor. Blood 111:969-70

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