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

Purpose 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. Methods We performed Balb/C (H-2d)-to-C57BL/6 (H-2b) 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. Results 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. Conclusion 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. 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. We performed Balb/C (H-2d)-to-C57BL/6 (H-2b) 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. 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. 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.