Nintedanib as an Anti-Fibrotic Therapy in a Mouse Model of Chronic Lung Allograft Dysfunction

Abstract

<h3>Purpose</h3> Chronic lung allograft dysfunction (CLAD) is the leading cause of lung transplant failure, with 50% of patients developing it by five years post-transplant. CLAD is characterized by progressive fibrosis, and it has no effective therapies. Nintedanib is a multiple tyrosine kinase inhibitor used to treat idiopathic pulmonary fibrosis. Here we assess nintedanib's efficacy, with tacrolimus, as a potential preventative CLAD therapy in the heterotopic tracheal transplant mouse model of CLAD-like airway fibrosis. <h3>Methods</h3> We performed Balb/C (H-2^d)-to-C57BL/6 (H-2^b) transplants. To arrive at effective doses of nintedanib and tacrolimus alone, we treated nine groups of n=10 recipients with one of three doses of nintedanib (0, 25, 50mg/kg), or six doses of tacrolimus (0, 0.1, 0.25, 0.5, 1, 2mg/kg). Mice were given either drug daily for 28 days. Following sacrifice, tracheas underwent Masson-Trichrome staining and were graded for luminal fibrotic occlusion and epithelial necrosis. Kruskal-Wallis one-way analyses of variance were performed on both grades within drug treatments. <h3>Results</h3> We found that compared to the control (Fig. 1C), fibrotic occlusion was significantly reduced in nintedanib treatment groups, but that epithelial necrosis was unaffected (Fig. 1 A, B, D). In contrast, we found that high doses of tacrolimus eliminated both pathologies (Fig. 1 A, B, E). Lower doses of tacrolimus had a moderate effect on luminal occlusion, and no effect on epithelial necrosis. <h3>Conclusion</h3> Our results demonstrate nintedanib's potential as an anti-fibrotic drug in lung transplantation. Nintedanib caused a significant decrease in fibrotic occlusion, but epithelial necrosis was reduced only by tacrolimus. Based on this, we will examine the combined effects of the drugs to arrive at a treatment strategy with both immunosuppressive and antifibrotic components.