Nintedanib reduces corticosteroid resistance pulmonary fibrosis induced by bleomycin in mice by increasing the expression of β3 & β6 integrins

Abstract

Background: Corticosteroid resistance pulmonary fibrosis is a major health problem. This study aimed to determine the effectiveness of nintedanib on corticosteroid resistance pulmonary fibrosis induced by bleomycin in mice. Methods: The mice were divided into five groups 12 mice each. control group, BLM group received single dose of bleomycin (BLM), BLM+MP group received BLM and methylprednisolone (MP), BLM+NIN group received BLM and nintedanib(NIN) and BLM + NIN + MP group. The lung tissues were obtained for biochemical analysis, gene expression and histopathological examination on day 7 and day 28. Results: after 7 days, both NIN groups showed a significant decrease in the levels of interleukin-2, interleukin-4, interferon-gamma, lung tumor necrosis factor-alpha, Malondialdehyde and lung water content with a significant increase in the Glutathione level in lung tissues compared to MP group. After 28 days, both NIN groups showed a significant reduction in hydroxyproline, and Trans-forming Growth Factor beta lung tissues contents compared to MP group, and they showed a positive effect on the expression of β 3 &β6 integrins compared to the negative effect of MP group. Histopathologically, both NIN groups showed significant improvement compared to MP group by H&E and Masson’s trichrome stains. Immunohistochemical staining revealed negative BCL-2 expression in the cytoplasm of bronchiolar epithelium in both NIN groups after 7 and 28 days of treatment. Lung tissue morphometric studies showed significant improvement of pathological changes induced by BLM in both NIN groups. Conclusions: Altogether, our data indicates that nintedanib overcame corticosteroid resistance pulmonary fibrosis induced by bleomycin.