Aurintricarboxylic acid mitigates cigarette smoke extract induced oxidative stress and pulmonary inflammation via inhibition of NF-ҡB/p65 signaling

Abstract

Cigarette smoke (CS) induced emphysema and chronic pulmonary inflammation are major comorbidities of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. CS exposure exacerbates pulmonary inflammation and compromises immunity to various infections. Aurintricarboxylic acid (ATA) is a polyanionic aromatic compound especially recognized for its anti-inflammatory, nucleic acid, and protein interaction inhibition properties. The study was designed to investigate the anti-inflammatory role of ATA against cigarette smoke extract (CSE) induced pulmonary inflammation. Nicotine concentration was quantified in CSE by UPLC/MS technique. In vitro, fluorescence microscopy, and flow cytometry was performed in CSE stimulated alveolar epithelial cells to determine the effect of ATA on oxidative stress-mediated cellular apoptosis. In vivo, pulmonary inflammation was induced in male Wistar rats via a modified non-invasive intratracheal instillation of cigarette smoke extract (100 µl/animal) twice a week for 8 weeks and post-treated with ATA (10 mg/kg) intraperitoneally for 15 days. Lung homogenates were assessed for MDA and GSH. Lung tissues were subjected to western blotting and histopathological analysis. As result, ATA reduced CSE-induced chromatin condensation, fragmentation, cellular apoptosis in alveolar epithelial cells, and apoptotic biomarkers expression including BAX and Caspase-3 in the lungs. ATA reduced inflammation by normalizing redox balance reflected by MDA/GSH levels. ATA obviated airspace enlargement, fiber deposition, and immune cell infiltration. Reduced inflammation was accompanied by inhibition of inflammatory biomarkers TNF-α, TNFR1, TWEAK, and NF-ҡB/p65 activation and nuclear translocation. ATA efficaciously diminished the oxidative stress and pulmonary inflammation associated with lung pathogenesis through TNF-α/TNFR1/NF-ҡB/p65 signaling pathway. HIGHLIGHTS ATA treatment attenuates CSE-stimulated chromatin condensation, fragmentation, and cellular apoptosis in alveolar epithelial cells. ATA treatment inhibits CSE stimulated activation and nuclear translocation of NF-ҡB/p65. ATA treatment diminishes CSE-induced oxidant injury, apoptosis, and emphysema-like phenotypic changes in the lungs. ATA inhibits lung inflammation via suppression of the NF-ҡB/p65 signaling pathway.