Effects Of Bone Marrow Mesenchymal Stem Cells And Cyclosporine On Experimental Bronchiolitis Obliterans

Objective: The main obstacle of long-term survival after lung transplantation is obliterative bronchiolitis(OB),Immunosuppressive medications within therapeutic classes has been the mainstay of therapy for bronchiolitis obliterans after lung transplantation,but the outcomes were disappointing;bone marrow mesenchymal stem cells(BMSCs) have been shown to be potent modulators of the immune response in many pulmonary conditions,so we used a orthotopic tracheal transplantation rats model to analysis and comparison the therapeutic effect of BMSCs and cyclosporine(Cs A)on OB.Methods: Orthotopic tracheal transplantation was performed in Brown Norway-to-Lewis, then treatment with BMSCs, Cs A and normal saline(NS). Tracheal grafts were harvested after 7, 30, and 60 days post-transplant, tracheal luminal obliteration and epithelial loss was assessed on sections stained with hematoxylin and eosin, CD4+and CD8+T lymphocyte in peripheral blood was assessed using flow cytometry, apoptosis of the grafts were detected by TUNEL,the expressing of transforming factor-beta1(TGF-β1) was measured by western blot and RT-PCR.Results: 1. The luminal obliteration in Cs A and BMSCs treated groups were significantly attenuated after 30 and 60 days post-transplant(p<0.01). 2. Cs A treatment was protective against the epithelial loss after 7, 30 days post-transplant compared with NS group(p<0.01), BMSCs treatment was more effective at epithelial preservation at 30 and 60 days after transplantation than Cs A treatment(p<0.01). 3.The CD4+ T lymphocyte in peripheral blood were significantly lower in Cs A treated group compared with BMSCs and NS treated groups(p<0.01), but CD8+T lymphocyte were significantly increased than BMSCs and NS treated groups(p<0.05). 4. BMSCs can effectively reduce the apoptosis of transplanted trachea. 5. Cs A and BMSCs showed decreased expression of TGF-β1 protein, and BMSCs was lower(p<0.01), but the both can not suppress the expression of TGF-β1m RNA.Conclusions: Both BMSCs and Cs A could prevent development of airway occlusion in a orthotopic tracheal transplantation mouse model of OB, BMSCs showed more effective at downregulating the expression of TGF-β1, lightening the apoptosis and the protection of epithelial loss. These results indicate that BMSCs could provide a novel therapeutic option to reduce chronic rejection after lung transplant.