Published ahead of print on May 11, 2007, doi:10.1164/rccm.200607-1004OC Am. J. Respir. Crit. Care Med., Volume 176, Number 4, August 2007, 385-394 A more recent version of this article appeared on August 15, 2007
Submitted on July 22, 2006 Engraftment of Bone Marrow Progenitor Cells in a Rat Model of Asbestos-Induced Pulmonary FibrosisJeffrey L Spees1*,1 Center for Gene Therapy, Tulane University Health Sciences Center, New Orleans, LA, USA; Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, VT, USA, 2 Department of Pathology and the Lung Biology Program, Tulane University Health Sciences Center, New Orleans, LA, USA, 3 Center for Gene Therapy, Tulane University Health Sciences Center, New Orleans, LA, USA * To whom correspondence should be addressed. E-mail: jeffrey.spees{at}uvm.edu.
Rationale: Bone marrow-derived cells have been shown to engraft during lung fibrosis. However, it is not known if similar cells engraft consequent to inhalation of asbestos fibers that cause pulmonary fibrosis, or if the cells proliferate and differentiate at sites of injury. Objectives: We examined whether bone marrow-derived cells participate in the pulmonary fibrosis that is produced by exposure to chrysotile asbestos fibers. Methods: Adult female rats were lethally-irradiated and rescued by bone marrow transplant from male transgenic rats ubiquitously expressing green fluorescent protein (GFP). Three weeks later, the rats were exposed to an asbestos aerosol for 5 hr on three consecutive days. Controls were bone marrow-transplanted but not exposed to asbestos. Measurements and Results: One day and 2.5 wk after exposure, significant numbers of GFP-labeled male cells had preferentially migrated to the bronchiolar-alveolar duct bifurcations, the specific anatomic site at which asbestos produces the initial fibrotic lesions. GFP-positive cells were present at the lesions as monocytes and macrophages, fibroblasts, and myofibroblasts or smooth muscle cells. Staining with antibodies to PCNA demonstrated that some of the engrafted cells were proliferating in the lesions and along the bronchioles. Negative results for TUNEL at the lesions confirmed that both PCNA-positive endogenous pulmonary cells and bone marrow-derived cells were proliferating rather than undergoing apoptosis, necrosis or DNA repair. Conclusion: Bone marrow-derived cells migrated into developing fibrogenic lesions, differentiated into multiple cell types, and persisted for at least 2.5 wks after the animals were exposed to aerosolized chrysotile asbestos fibers. Key words: bone marrow, progenitor cell, asbestos, fibrosis
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