Efeito do tratamento com nanopartículas de ouro sobre a resposta fibrótica pulmonar induzida por bleomicina em camundongos

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease, characterized by infiltration of inflammatory cells, hyperplasia of alveolar epithelial cells, and recruitment of fibroblasts and fibrosis, representing a challenge for health services due to the lack of effective therapy. Evidence indicates that gold nanoparticles (AuNPs) have important anti-inflammatory properties, which qualifies them as a therapeutic option for lung disorders. In this study, we investigated the effect of the therapeutic administration of AuNPs on inflammation and pulmonary fibrosis induced by bleomycin in mice, a model that reproduces the clinical picture of idiopathic pulmonary fibrosis (IPF). C57/Bl6 mice stimulated through oropharyngeal aspiration of bleomycin (0.06 U/40 µL) and treated with an aerosol of AuNPs (0.15 - 1.5 µg/mL) on days 14, 17 and 20 post-treatment were used. bleomycin and analyzes were performed 1 day after the last dose. Parameters assessed included i) assessment of lung function and airway hyper-reactivity using invasive whole-body plethysmography; ii) morphological analysis using standard histological techniques; iii) quantification and qualification of collagen by Sircol and western blotting; iv) oxidative stress markers by biochemical analysis; and v) quantification of cytokines and chemokines by ELISA. We found that mice stimulated with bleomycin exhibited an increase in lung resistance and elastance, as well as airway hyperreactivity. We also observed, in the lungs of these animals, the presence of an inflammatory infiltrate, collagen deposition, with a clear predominance of type I compared to type III. Increased production of reactive oxygen species (ROS), decreased activity of antioxidant enzymes (SOD and CAT), as well as increased levels of malondialdehyde (MDA) and the transcription factor NRF2, were detected after stimulation with bleomycin. Furthermore, we saw an increase in the production of cytokines (IL-6, IL-1β e TGF-β) and chemokines (KC, MCP-1 and MIP-1α). The therapeutic administration of AuNPs, to mice previously challenged with bleomycin, was able to restore respiratory function and attenuated the pulmonary fibrosis condition by reducing the levels of type I collagen. We also observed a decrease in the production of cytokines and chemokines, recovery of the activity of the antioxidant enzyme CAT, reduction of oxidative MDA levels, and increase of the NRF2 transcription factor. Taken together, our findings show that treatment with AuNPs reduced the inflammatory and fibrogenic components in the lung of mice challenged with bleomycin, suggesting that AuNPs seem to constitute a promising therapeutic approach for application in fibrotic lung diseases such as IPF