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Bone Marrow Origin of Myofibroblasts in Irradiation Pulmonary Fibrosis.pdf

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Bone Marrow Origin of Myofibroblasts in Irradiation Pulmonary Fibrosis

Bone Marrow Origin of Myofibroblasts in Irradiation Pulmonary Fibrosis Michael W. Epperly, Hongliang Guo, Joan E. Gretton, and Joel S. Greenberger Department of Radiation Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 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 fluo- rescent 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 contribu- tion of Y-probe–positive, GFP cells to fibrotic areas was quanti- tated. Bromodeoxyuridine labeling of developing fibrotic areas showed that the cell division occurred predominantly in GFP, Y-probe–positive, and vimentin-positive cells. Immunohisto- chemistry 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 de- creasing the migration and proliferation of marrow origin cells. Irradiation-induced pulmonary damage is a major complica- tion in patients who receive total body irradiation for bone marrow transplantation and in patients receiving lung irra- diation for esophagus or non–small cell lung carcinoma (NSCLC) (1, 2). In both human and animal model systems, acute pneumoni