Bone Marrow Origin of Myofibroblasts in Irradiation Pulmonary Fibrosis

Abstract

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.

Mobilization of Bone Marrow Stem Cells by Granulocyte Colony-Stimulating Factor Ameliorates Radiation-Induced Damage to Salivary Glands

“…This is in agreement with results described in a study using an ischemia/reperfusion model of kidney damage (45). Moreover, like us, they also showed the presence of bone marrow -derived myofibroblasts cells in the interstitium, which is also known to occur after a radiation insult (27).…”

CCR2-Mediated Recruitment of Fibrocytes to the Alveolar Space after Fibrotic Injury

“…21,22 Neither of these studies characterized the GFP ϩ fibroblasts for fibrocyte markers. Our work is the first to demonstrate that bone marrow precursors give rise to CD45 ϩ , CD13 ϩ , col 1 ϩ , CCR2 ϩ lung fibrocytes.…”

“…21,22 CCR2 Ϫ/Ϫ mice were lethally irradiated and reconstituted with a BMT from CCR2 ϩ/ϩ mice. Mice were allowed to recover from the BMT for at least 7 weeks.…”

Stem cells and cell therapies for cystic fibrosis and other lung diseases

“…Circulating fibrocytes, adult marrow-derived cells that express both hematopoietic and myofibroblast markers, have been implicated in smooth muscle and myofibroblasts proliferation in both asthma and in pulmonary fibrosis [25][26][27]. This suggests a specific target for therapeutic intervention, ie., blocking recruitment and engraftment of fibrocytes in lung.…”