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

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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 (5 mg/kg) in rats then treatments were administered 14 days thereafter. Nintedanib (100 mg/kg, I.P.) was administered daily for 28 days, while BM-MSCs were injected once intravenously in tail vein in the dose 1 × 106 cells/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.

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Acknowledgments

The technical assistance of the Professor of Pathology Sahar S Abd El-Rahman, Faculty of Veterinary Medicine, Cairo University is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt

    E. S. Gad

  2. Department of Pharmacology, National Research Centre, Cairo, Egypt

    A. A. A. Salama

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt

    M. F. El-Shafie

  4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Ahram Canadian University, Cairo, Egypt

    H. M. M. Arafa

  5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    R. M. Abdelsalam & M. Khattab

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  1. E. S. Gad
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Correspondence to E. S. Gad.

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All experimental procedures were approved by the research ethics committee at Faculty of Pharmacy, Cairo University, Egypt in accordance with “Guide for the Care and Use of Laboratory Animals,” 1996.

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Gad, E.S., Salama, A.A.A., El-Shafie, M.F. et al. The Anti-fibrotic and Anti-inflammatory Potential of Bone Marrow–Derived Mesenchymal Stem Cells and Nintedanib in Bleomycin-Induced Lung Fibrosis in Rats. Inflammation 43, 123–134 (2020). https://doi.org/10.1007/s10753-019-01101-2

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