Background: Obliterative bronchiolitis (OB) is the major obstacle limiting long-term allograft survival of lung transplantation. Airway epithelium is the primary target in obliterative airway diseases. The roles of neutrophils during inflammatory responses and OB pathogenesis after lung transplantation remain largely unknown. In this study, we utilized murine orthotopic trachea transplantation models to examine the roles of neutrophil-mediated immune responses in airway epithelial injury and OB pathogenesis.

Methods: Murine orthotopic allogenic trachea transplants were performed in wild type C57BL/6 mice using BALB/c donors. For neutrophil suppression, recipients received 300[mu]g of CXCR1/2 inhibitor (Reparixin) i.p. daily on days -1 to 7. Syngeneic transplants were also performed in wild type C57BL/6 mice using C57BL/6 donors. Histopathology was employed on transplanted tracheas to examine airway epithelial injury and inflammatory cell infiltration. Real-time RT-PCR was performed for measuring the expression of inflammatory cytokines and chemokines in trachea grafts.

Results: The expression levels of inflammatory cytokines and chemokines, IL-17, IL-6, IL-8 and CXCL1, were significantly elevated in allografts 3 days after transplantation. At day 14, the airway structure of isografts resembles normal trachea morphology, while the pseudostratified ciliated columnar epithelia of allografts changed into flat epithelia with fibroblast proliferation and inflammatory cell infiltration in submucosal tissue. Reparixin treatment facilitated pseudostratified epithelial restoration and attenuated inflammatory cytokine and chemokine production.

Conclusions: Inhibition of neutrophil recruitment and activation by CXCR1/2 inhibitor reduces airway epithelial injury and inflammatory responses after transplantation. Our data identify a detrimental role of migrating neutrophils after transplantation and indicate a novel therapeutic approach for airway epithelial damage and allograft rejection.

CITATION INFORMATION: Zhang R., Fang H., Chen Q., Ochando J., Ding Y., Xu J. Inhibition of Neutrophil Recruitment and Activation Protects Airway Epithelium after Transplantation Am J Transplant. 2017;17 (suppl 3).

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