esculetin and Asthma

Airway remodeling is one important feature of childhood asthma, which is one of the most common chronic childhood diseases. Phenotype switching of airway smooth muscle cells (ASMCs), defined as a reversible switching between contractile and proliferative phenotypes, plays an important role in the process of airway remodeling. Esculetin has shown antiinflammatory action in animal models of asthma; however, the effects of esculetin on ASMC phenotype switching have not been investigated. In the present study, platelet-derived growth factor (PDGF) was used to induce the phenotype modulation of ASMCs. The results demonstrated that esculetin pretreatment mitigated the PDGF-caused inhibitory effects on expressions of contractile phenotype protein markers, including calponin and SM22α. Esculetin also inhibited PDGF-induced migration and proliferation of ASMCs. Besides, the PDGF-induced expressions of extracellular matrix components, collagen I and fibronectin, were attenuated by esculetin pretreatment. Furthermore, PDGF-caused activation of PI3K/Akt pathway in ASMCs was inhibited by esculetin. These findings suggest that esculetin might exert its inhibitory effect on PDGF-induced ASMC phenotype switching through inhibition of PI3K/Akt pathway.

Topics: Airway Remodeling; Asthma; Cell Movement; Cell Proliferation; Cell Transdifferentiation; Cells, Cultured; Child; Collagen Type I; Humans; Muscle Contraction; Myocytes, Smooth Muscle; Phenotype; Phosphatidylinositol 3-Kinases; Platelet-Derived Growth Factor; Respiratory Mucosa; Umbelliferones

The purpose of the current study was to investigate the anti-asthmatic effect of esculetin (ES) and explore its potential mechanism with a mouse model of allergic asthma. A total number of 50 mice were randomly assigned to five groups: control, model, dexamethasone (Dex, 2 mg/kg), and ES (20 mg/kg, 40 mg/kg). Mouse asthma model was developed with the sensitization and challenge of ovalbumin (OVA). The levels of IgE in serum, eosinophilia infiltration, Th2/Th17 cytokines, Th17 cell frequency, histological condition, and the protein expressions of RORγt, GATA3 were detected. Our study demonstrated that ES inhibited, OVA-induced eosinophil count, interleukin-4 (IL-4), IL-5, IL-13, and IL-17A levels were recovered in bronchoalveolar lavage fluid. Flow cytometry (FCM) studies revealed that ES substantially inhibited Th17 cells' percentage. Western blot study also indicated that ES downregulated RORγt and GATA3 expressions. Meanwhile, ES had beneficial effects on the histological alteration. These findings suggested that ES might effectively ameliorate the progression of asthma and could be used as a therapy for patients with allergic asthma.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Dexamethasone; Disease Models, Animal; Eosinophilia; Female; GATA3 Transcription Factor; Immunoglobulin E; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Lymphocyte Count; Mice; Mice, Inbred BALB C; Nuclear Receptor Subfamily 1, Group F, Member 3; Ovalbumin; Random Allocation; Th17 Cells; Th2 Cells; Umbelliferones

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.

Topics: Animals; Anti-Asthmatic Agents; Antioxidants; Asthma; Bronchial Hyperreactivity; Electron Transport Complex IV; Fibrosis; Lipoxygenase Inhibitors; Mice; Mitochondrial Diseases; Transforming Growth Factor beta1; Treatment Outcome; Umbelliferones