Esculetin restores mitochondrial dysfunction and reduces allergic asthma features in experimental murine model.
We recently showed that IL-4-dependent oxidative stress and mitochondrial dysfunction are associated with allergic asthma. IL-4 also induces a prooxidant enzyme, 15-lipoxygenase, which predominantly expresses in asthmatic bronchial epithelium and degrades mitochondria. Esculetin (6,7-dihydroxy-2H-1-benzopyran-2-one), a plant-derived coumarin and immunomodulator, was found to have potent bronchodilating property in carbachol-induced bronchoconstriction and also reduces mitochondrial dysfunction in neurological diseases. In this study, we evaluated its potential in restoring mitochondrial dysfunction and structural changes and anti-asthma property in a mouse model of experimental asthma. In this study, we found that esculetin treatment reduced airway hyperresponsiveness, Th2 response, lung eotaxin, bronchoalveolar lavage fluid eosinophilia, airway inflammation, and OVA-specific IgE. It also reduced the expression and metabolites of 15-lipoxygenase and lipid peroxidation which is an essential prerequisite for mitochondrial dysfunction. Interestingly, esculetin treatment restored the activity of cytochrome c oxidase of electron transport chain in lung mitochondria and expression of the third subunit of cytochrome c oxidase of electron transport chain in bronchial epithelium. It reduced the cytochrome c level and caspase 9 activity in lung cytosol and restored mitochondrial structural changes and lung ATP levels. In addition, esculetin reduced subepithelial fibrosis and TGF-beta1 levels in the lung. These results suggest that esculetin not only restores mitochondrial dysfunction and structural changes but also alleviates asthmatic features.
Mabalirajan
Ulaganathan
U
Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi, India.
Dinda
Amit Kumar
AK
Sharma
Surendra Kumar
SK
Ghosh
Balaram
B
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D003576:Electron Transport Complex IV / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy; D016859:Lipoxygenase Inhibitors; D051379:Mice; D028361:Mitochondrial Diseases / Q000188:drug therapy*; D053773:Transforming Growth Factor beta1 / Q000187:drug effects; D016896:Treatment Outcome; D014468:Umbelliferones / Q000494:pharmacology* / Q000627:therapeutic use
D018927:Anti-Asthmatic Agents; D000975:Antioxidants; D016859:Lipoxygenase Inhibitors; D053773:Transforming Growth Factor beta1; D014468:Umbelliferones; D003576:Electron Transport Complex IV; C007628:esculetin