Repositioning itraconazole for amelioration of bleomycin-induced pulmonary fibrosis: Targeting HMGB1/TLR4 Axis, NLRP3 inflammasome/NF-κB signaling, and autophagy

Background and aims: Bleomycin (BLM) is one of the antitumor medications that had proven efficacy in the treatment of a wide range of malignant conditions. Pulmonary fibrosis which is frequently encountered during the course of bleomycin therapy may significantly reduce the potential efficacy of bleomycin in cancer therapy. This study tested the hypothesis that itraconazole may have mitigating effects on BLM-induced pulmonary fibrosis and tried to delineate the potential mechanisms of these effects. Materials and methods: In a rat model of pulmonary fibrosis elicited by BLM, the effect of different doses of itraconazole was explored at the biochemical, histopathological, and electron microscopic levels. Key findings: Itraconazole, in a dose-dependent manner, exhibited significant effects on the pro-oxidant/ antioxidant balance, the inflammatory consequences, high-mobility group box 1/toll-like receptor-4 Axis, autophagy and nuclear factor kappa B/Nod-like receptor protein 3 inflammasome signaling and alleviated the histopathological, immunohistochemical, and electron microscopic perturbations induced by BLM in the pul-monary tissues. Significance: In view of the afore-mentioned data, itraconazole may be a promising drug that efficiently mitigates the deleterious effects of BLM on the pulmonary tissues.

Automated summary

This study investigated the potential mitigating effects of itraconazole on bleomycin-induced pulmonary fibrosis and explored the underlying mechanisms. The results showed that itraconazole had significant effects on oxidative stress, inflammation, high-mobility group box 1/toll-like receptor-4 Axis, autophagy, and nuclear factor kappa B/Nod-like receptor protein 3 inflammasome signaling. It also alleviated the histopathological, immunohistochemical, and electron microscopic abnormalities in pulmonary tissues. Therefore, itraconazole may be a promising drug to mitigate the deleterious effects of bleomycin on the lungs.