Prevention of the second stage of epithelial loss is a potential novel treatment for bronchiolitis obliterans

Abstract

Loss of epithelial cells is one of the key factors that lead to airway fibrosis. Loss of epithelial cells may decrease the barrier to host cell infiltration into the lumen, allowing deposition of extracellular matrix, with subsequent obliteration of the airway. The objective of this study was to determine whether injection of epithelial cells/progenitor cells from the recipient into the lumen of the donor trachea could prevent bronchiolitis obliterans (BO) in a mouse heterotopic tracheal transplantation (HTT) model. A major histocompatibility complex class I and class II mismatch of mouse HTT model of BO was used. Epithelial cells from recipient mice were isolated and reinjected into the lumen of the allografts on day 3 after transplantation. Rag-1 knock-out and isografts were also performed as controls. The grafts were analyzed by immunohistochemistry and densitometric analysis. The results demonstrated that tracheal epithelium was lost by day 3, regenerated between 3 to 7 days, and was lost again in all allografts, but not in the isografts or in Rag-1 knock-out groups by day 12. The reconstituted epithelium was donor originated on day 7 based on green fluorescent protein staining. Furthermore, with the injection of recipient cells into the tracheal lumen, loss of the epithelium was not observed and the luminal obliteration was significantly less in the allografts. Injection of recipient epithelial cells prevents the second phase of epithelial loss and significantly decreases BO development in an HTT model. Clinically, the use of injected recipient epithelial cells could be a novel treatment for BO.