Receptor Tyrosine Kinase Inhibitor Nintedanib as Treatment Option in Bronchiolitis Obliterans after Airway Transplantation

Abstract

Purpose The major obstacle for long-term survival after successful lung transplantation is the development of chronic lung allograft dysfunction (CLAD). It has been shown that nintedanib, an intracellular inhibitor of receptor tyrosine kinases, has a beneficial effect in the treatment of neoplastic diseases and idiopathic pulmonary fibrosis. Nintedanib influences three major angiogenic signalling pathways by blocking the receptors for: platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). Furthermore, these receptors play an important role in the development of CLAD after lung transplantation. Therefore, the aim of this study was to determine the effect of nintedanib on the development of obliterative bronchiolitis (OB) after orthotopic trachea transplantation in a mouse model. Methods Allogenic donor trachea grafts from C57BL/6 mice (H2b) were transplanted into CBA mice (H2k) in orthotopic position. Afterwards, recipients were treated with nintedanib (60 mg/kg/d) from day 1 and from day 14, respectively. Histological measurements and immunofluorescence analyses were performed after 30 days. In the PCR group the treatment was performed from day 1 and quantitative intragraft gene expression analyses were conducted after 14 days. n=7/group Results Tracheal allografts treated daily with nintedanib showed significant less obliteration vs. untreated grafts reflected in a higher epithelium lamina propria ratio (ELR) [ELR: nintedanib treated allografts 0,68 vs. 0,50 in untreated grafts; p Conclusion These results demonstrate that the blocking of the tyrosine kinase receptors by nintedanib seems to be a promising tool to inhibit the development of chronic rejection in lung transplants even by delayed treatment -representative of a clinical setting- nintedanib prevents the progression of obliterative bronchiolitis.