Histopathology of ARDS is defined as diffuse alveolar damage (DAD). Antemortem evidence for fibroproliferation directly correlates with risk of death in ARDS, and postmortem findings in the lungs of patients who died of ARDS demonstrate increased fibroproliferation. Fibroblasts are the major cellular source of extracellular matrix. However, the origin of the interstitial fibroblast that contributes to fibrosing alveolitis during DAD remains to be elucidated. Our preliminary data demonstrates that circulating fibrocytes play a significant role in promoting the fibrosing alveolitis of Acute lung injury (ALI). We hypothesize that circulating fibrocytes, mobilized from a bone marrow (BM) precursor cell, extravasate into the lung by a chemokine-dependent (CXCL12/CXCR4) mechanism, differentiate to tissue myofibroblasts, and contribute to fibroproliferative response of ALI. To test this hypothesis, we will perform experiments in the following Specific Aims I. A) To determine the origin of circulating fibrocytes and whether they are derived from a BM progenitor cell. B) To demonstrate that the temporal mobilization of BM progenitor fibrocytes, extravasation of circulating fibrocytes, and differentiation into myofibroblasts directly correlates with the fibroproliferative phase of ALI. II. A) To determine whether factor(s) generated in the lung promote mobilization of BM precursor fibrocytes and increase the pool of circulating fibrocytes during ALI. B) To establish that the temporal expression of CXCL12 directly correlates with the kinetics of extravasating fibrocytes in the lung during ALI. C) To ascertain whether homing and extravasation of circulating fibrocytes into the lung during ALI is dependent on CXCL12/CXCR4. D) To establish whether combined inhibition of BM precursor fibrocyte mobilization and recruitment of circulating fibrocytes leads to additive or synergistic attenuation of the fibroproliferative response during ALI. III. A) To establish whether hypoxia-inducible factor-1 alpha (HIF-1alpha) regulates the expression of CXCR4 on BM progenitor fibrocytes and circulating fibrocytes. B) To determine whether fibrocytes derived from BM precursor cells genetically HIF-1alpha null or von Hippel-Lindau tumor suppressor protein (VHL) null correlate with altered CXCR4 expression and recruitment to the lung during ALI. IV. A) To ascertain whether chemokine signaling through phosphoinositide 3-kinase (PI3K) is critical to fibrocyte migration, proliferation, and survival in vitro. B) To determine whether fibrocytes derived from BM precursor cells genetically devoid of PI3K (PI3Kgamma-/-) have impaired homing, extravasation, proliferation, and survival in the lung during ALI. The findings of these studies may lead to novel intervention to attenuate the fibroproliferation and reduce morbidity and mortality related to ARDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066027-08
Application #
7162137
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2001-02-01
Project End
2009-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
8
Fiscal Year
2007
Total Cost
$359,123
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Choi, Young H; Burdick, Marie D; Strieter, Brett A et al. (2014) CXCR4, but not CXCR7, discriminates metastatic behavior in non-small cell lung cancer cells. Mol Cancer Res 12:38-47
Field, Joshua J; Burdick, Marie D; DeBaun, Michael R et al. (2012) The role of fibrocytes in sickle cell lung disease. PLoS One 7:e33702
Keeley, Ellen C; Mehrad, Borna; Strieter, Robert M (2011) Chemokines as mediators of tumor angiogenesis and neovascularization. Exp Cell Res 317:685-90
Struyf, Sofie; Salogni, Laura; Burdick, Marie D et al. (2011) Angiostatic and chemotactic activities of the CXC chemokine CXCL4L1 (platelet factor-4 variant) are mediated by CXCR3. Blood 117:480-8
Keeley, Ellen C; Moorman, J Randall; Liu, Ling et al. (2011) Plasma chemokine levels are associated with the presence and extent of angiographic coronary collaterals in chronic ischemic heart disease. PLoS One 6:e21174
Keeley, Ellen C; Mehrad, Borna; Strieter, Robert M (2010) Fibrocytes: bringing new insights into mechanisms of inflammation and fibrosis. Int J Biochem Cell Biol 42:535-42
Shim, Y Michael; Paige, Mikell; Hanna, Halim et al. (2010) Role of LTB? in the pathogenesis of elastase-induced murine pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol 299:L749-59
Choi, Young H; Burdick, Marie D; Strieter, Robert M (2010) Human circulating fibrocytes have the capacity to differentiate osteoblasts and chondrocytes. Int J Biochem Cell Biol 42:662-71
Strieter, Robert M; Mehrad, Borna (2009) New mechanisms of pulmonary fibrosis. Chest 136:1364-1370
Strieter, Robert M; Keeley, Ellen C; Hughes, Molly A et al. (2009) The role of circulating mesenchymal progenitor cells (fibrocytes) in the pathogenesis of pulmonary fibrosis. J Leukoc Biol 86:1111-8

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