Abstract

Background:  Pulmonary fibrosis is a progressive lung disorder that occurs by lung injury and scarring of the lung tissue. This injury makes the lung thickened and stiff causing difficulty to breathe.  Corticosteroid resistance pulmonary fibrosis is a major health problem. Bleomycin is an anti-cancer agent, it induces pulmonary fibrosis resistance to corticosteroid therapy, this study aimed to determine the effectiveness of nintedanib (NIN) a tyrosine kinase inhibitor on corticosteroid resistance pulmonary fibrosis induced by bleomycin in mice.
Methods: Sixty albino male adult mice were used in this study. The mice were divided into five groups (n=12) at random. control group, the BLM group received a single dose of bleomycin (BLM); 2U/kg by endotracheal instillation, the BLM+MP group received bleomycin and methylprednisolone (MP) 10mg/kg/day by gastric gavage, BLM+NIN group received BLM and NIN, 60mg/kg/day by gastric gavage and the combined treatment group received BLM, NIN, and MP. All groups were sacrificed after the last dose of treatment on day 7 (acute stage) and day 28 (chronic stage). The lung tissues were obtained for biochemical analysis, gene expression, and histopathological examination at the end of the experiment.
Results: After 7 days of treatments, BLM+NIN   and BLM + NIN + MP groups showed a significant (P<0.05) decrease in the contents of interleukin-2, interleukin-4, interferon-gamma, tumor necrosis factor-alpha, Malondialdehyde with an increase in the glutathione content in lung tissue compared to MP group. Also, they showed a significant decrease in the lung water content compared to the BLM group treated with MP. After 28 days, both NIN groups showed a significant reduction in hydroxyproline, and transforming growth factor beta (β) contents in the lung tissues compared to the MP group, and they showed a positive effect on the expression of β3 and β6 integrins compared to the negative effect of the MP group.   Upon histopathology examination, the BLM+NIN group and BLM + NIN + MP groups showed significant improvement compared to the MP group by hematoxylin and eosin (H and E) and Masson’s trichrome stains. Immunohistochemical staining revealed negative BCL-2 expression in the cytoplasm of bronchiolar epithelium in BLM+NIN and BLM + NIN + MP groups after 7 and 28 days of treatment. Morphometric studies of lung tissue showed significant improvement in pathological changes induced by BLM in the BLM+NIN group and BLM + NIN + MP groups.
Conclusion: Altogether, our data indicate that NIN overcame corticosteroid resistance pulmonary fibrosis induced by bleomycin in mice mainly by decreasing TGF-β and improving the expression of β3 and β6 integrins.

Keywords

Pulmonary fibrosis, Corticosteroid resistance, Nintedanib, Integrins, Bleomycin.

How to Cite