The activity of nintedanib in an animal model of allogenic left lung transplantation resembling aspects of allograft rejection

ABSTRACT

Aim of the Study: The prevention and treatment of chronic lung allograft dysfunction (CLAD) after lung transplantation (LTx) remain unsatisfactory. Growth factors may play an important role in the development of CLAD. This study evaluated the effects of nintedanib, a receptor tyrosine kinase inhibitor, in the treatment of CLAD after experimental LTx. Materials and Methods: A rat model of left lung allo-transplantation (Fisher 344 to Wistar Kyoto) was used to evaluate the effect of nintedanib (50 mg/kg per day) on the development of CLAD. Therapy with nintedanib began 2 days before LTx and ended on postoperative day (POD) 20 (n = 6) or 60 (n = 6). Nontreated animals who underwent LTx (n = 12) were used as controls, whereas naïve lungs (n = 24) served as reference for physiological healthy organs without transplantation damage or medical effects. Acute and chronic rejection were evaluated on POD 20 and 60, respectively. Results: Immunohistologic analysis showed a decrease in growth factors/receptors on POD 60 (nintedanib-treated vs. nontreated controls: platelet-derived growth factor (PDGF) A: [P ≤ 0.001]; PDGF receptor-α: [P ≤ 0.001]; vascular endothelial growth factor (VEGF) A: [P ≤ 0.001]; VEGF receptor-2: [P ≤ 0.001]). However, no reductions in fibrotic changes were observed in nintedanib-treated allografts compared with nontreated allografts. Although nintedanib treatment started before LTx none of the animals showed impaired wound healing. No dehiscence of the sutures of the bronchus, vessels or skin, or stenosis of the bronchus was found. Conclusion: In conclusion, while nintedanib reduced the expression of growth factors/receptors in a rat LTx model, a reduction in fibrotic alterations was not observed at POD 60.

KEYWORDS:

• Chronic lung allograft rejection
• CLAD
• immunochemistry
• organ transplant
• tyrosine kinase

Acknowledgments

Editorial assistance, supported financially by Boehringer Ingelheim, was provided by Julie Fleming of FleishmanHillard Fishburn, London, UK, during the preparation of this article. The authors were fully responsible for all content and editorial decisions, were involved at all stages of manuscript development, and have approved the final version of the manuscript, which reflects the authors’ interpretation and conclusions.

Declaration of interest

Lutz Wollin is an employee of Boehringer Ingelheim the inventor of nintedanib used in this study.

Funding

The study was supported by Boehringer Ingelheim Pharma, Germany.