The Anti-fibrotic and Anti-inflammatory Potential of Bone Marrow-Derived Mesenchymal Stem Cells and Nintedanib in Bleomycin-Induced Lung Fibrosis in Rats.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive lung damage. Tyrosine kinase inhibitors are approved to treat people with IPF while bone marrow-derived mesenchymal stem cell therapy was previously suggested to inhibit pulmonary fibrosis through the alveolar epithelial cell repair. The present study aimed to evaluate the anti-inflammatory and anti-fibrotic effect of the bone marrow-derived mesenchymal stem cell (BM-MSC) therapy in comparison with nintedanib, a tyrosine kinase inhibitor, on improving survival in bleomycin-induced lung fibrosis in rats. Moreover, the combined therapy of BM-MSCs and nintedanib will be evaluated. In the present study, IPF was induced through intra-tracheal instillation of bleomycin (5mg/kg) in rats then treatments were administered 14days thereafter. Nintedanib (100mg/kg, I.P.) was administered daily for 28days, while BM-MSCs were injected once intravenously in tail vein in the dose 1 × 106cells/ml/rat. In the present study, both treatment regimens effectively inhibited lung fibrosis through several pathways, suppressing tumor growth factor-β (TGF-β)/SMAD3 expression which is considered the master signaling pathway. Nintedanib and BLM-MSCs exerted their anti-inflammatory effect through minimizing the expression of TNF-α and IL-6. In addition, the histopathological examination of the lung tissue showed a significant decrease in the alveolar wall thickening, in the inflammatory infiltrate, and in the collagen fiber deposition in response to either nintedanib or BM-MSC and their combination. In conclusion, the therapeutic pulmonary anti-fibrotic activity of nintedanib or BM-MSC is mediated through their anti-inflammatory properties and inhibition of SMAD-3/TGF-β expression.