Prevent or Treat? Evaluating a Delayed Treatment With Nintedanib After Murine Orthotopic Tracheal Transplantation.

Abstract

Background: Chronic lung allograft dysfunction significantly impairs long-term lung transplant survival. Bronchiolitis obliterans syndrome is a chronic lung allograft dysfunction phenotype characterized by fibroproliferative changes in noncartilaginous airways. We previously demonstrated that the tyrosine kinase inhibitor nintedanib reduces chronic airway changes in murine tracheal allografts. In this study, we investigated whether delayed treatment, similar to the clinical scenario following lung transplantation, would still be beneficial.

Methods: Recipient CBA/JRj mice received orthotopic tracheal transplants from donor C57BL/6JRj mice. A dosage of 60 mg/kg of nintedanib was administered orally to transplanted mice every day between days 14 and 29 after transplantation. Histological and immunofluorescence analyses, as well as intragraft gene expression measurements, were performed after 14 and 30 d.

Results: Delayed-treated tracheal allografts (nintedanib 14-30) exhibited less evidence of chronic rejection than untreated allografts on day 30 (control 30). This is demonstrated by an increased epithelium-to-lamina propria ratio (0.62 ± 0.16 [nintedanib 14-30] versus 0.50 ± 0.01 [control 30]; P < 0.05), with a reduction in CD4⁺ T cell, dendritic cell, and macrophage infiltration. Furthermore, intragraft gene expression of inflammatory cytokines, adhesion molecules, and growth factors was also lowered. While allografts treated immediately (nintedanib 30) demonstrated a comparable epithelium-to-lamina propria ratio to the nintedanib 14-30 group, earlier treatment resulted in considerably lower infiltration of CD4⁺ and CD8⁺ T cells as well as alpha smooth muscle actin expression.

Conclusions: Even delayed nintedanib therapy has an attenuating effect on chronic inflammation but is less effective regarding the fibroproliferative changes that are considered a sign of chronic airway changes after murine tracheal transplantation. Thus, it may serve as supportive therapy in the clinical setting after lung transplantation, but earlier initiation might be more effective.