AhR activation plays a detrimental role in airway epithelial injury after transplantation

Abstract

Abstract Patients with tracheal tumors, trauma, infection, congenital malformations or injury after prolonged intubation may require partial or complete tracheal resection, and tracheal transplantation will be necessary when the length of resected trachea is longer than 30% in children or 50% in adults. Currently, obliterative bronchiolitis (OB) is a major obstacle that affects allograft function and survival after tracheal transplantation. Th17 polarization and inflammatory cytokine expression is crucially involved in airway transplant rejection, and activation of aryl hydrocarbon receptor (AhR) could modulate Th17 differentiation and inflammatory cytokine production. However, the role of AhR signal pathway in airway epithelial injury, a leading factor of OB development, after transplantation remains unclear. In this study, we performed murine orthotopic tracheal transplants in C57BL/6 wild type mice using BALB/c donors. The levels of IFNγ, IL-6 and IL-17 expression were significantly elevated in allografts, and the airway pseudostratified epithelia changed into flat epithelia with inflammation and fibroblast proliferation in submucosa tissue. Allografts of recipients administered with AhR antagonist (CH-223191) displayed inhibition of IL-17 and IFNγ, and some airway epithelial protection. Significant lamina fibrosis and higher levels of inflammatory cytokine production was observed in allografts of recipients administered with AhR agonist (FICZ). Together, our results demonstrate that AhR activation plays a detrimental role in airway epithelial injury after transplantation, pointing to a new therapeutic avenue for benefitting airway allograft survival through manipulating AhR pathway.