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Bone Marrow Origin of Myofibroblasts in Irradiation Pulmonary Fibrosis

Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania

Address correspondence to: Joel S. Greenberger, M.D., Professor and Chairman, Department of Radiation Oncology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Room B346-PUH, Pittsburgh, PA 15213. E-mail: greenbergerjs{at}msx.upmc.edu

There is a rapid onset of organizing alveolitis/fibrosis at 120–140 d after whole lung irradiation of C57BL/6J mice. To test the hypothesis that circulating cells of bone marrow origin contribute to irradiation fibrosis, irradiated chimeric green fluorescent protein (GFP)+ C57BL/6J mice were followed for GFP+ cells in areas of lung fibrosis. In a second experimental model, C57BL/6J female mice received 20 Gy total lung irradiation, and after 60 or 80 d were intravenously injected with cells from a clonal GFP+ male bone marrow stromal cell line or male GFP+ whole bone marrow, respectively. The mice were then followed for the development of pulmonary fibrosis, and the contribution of Y-probe–positive, GFP+ cells to fibrotic areas was quantitated. Bromodeoxyuridine labeling of developing fibrotic areas showed that the cell division occurred predominantly in GFP+, Y-probe–positive, and vimentin-positive cells. Immunohistochemistry demonstrated that these cells were macrophages and fibroblasts, not endothelial cells. Mice that received manganese superoxide dismutase-plasmid/liposome intratracheal injection 24 h before total lung irradiation demonstrated a decrease in GFP+ fibroblastic cells in the lung. Thus, pulmonary irradiation fibrosis contains proliferating cells of bone marrow origin, and gene therapy prevention of this condition acts in part by decreasing the migration and proliferation of marrow origin cells.

Abbreviations: bromodeoxyuridine, BrdU • green fluorescent protein, GFP • intracellular adhesion molecule, ICAM • manganese superoxide dismutase, MnSOD • optimum cutting temperature, OCT • phosphate-buffered saline, PBS • plasmid/liposome, PL • vascular cell adhesion molecule, VCAM

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