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

Objectives: The major issue for long-term survival after successful lung transplantation is the development of bronchiolitis obliterans syndrome (BOS) one phenotype of chronic lung allograft dysfunction leading to organ failure. Further research is necessary to treat this disease in transplant recipients. 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 signaling 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 BOS 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 (H2^b) were transplanted into CBA mice (H2^k) in orthotopic position. Afterward, recipients were treated with nintedanib (60 mg/kg/d) from days 1 and 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 < 0.05). Even a delayed treatment with nintedanib led to a better ELR compared with untreated animals (ELR delayed: 0.63; p < 0.05). These results were supported by lower immigration of macrophages into the submucosa (10.96 vs. 25.18% untreated; p < 0.05). Additionally, the detection of both PDGF receptor subtypes within the grafts was decreased in the treated group. This correlates with the expression analyses of PDGFR α and PDGFR β.

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.