Esculetin Restores Mitochondrial Dysfunction and Reduces Allergic Asthma Features in Experimental Murine Model

Abstract

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-β1 levels in the lung. These results suggest that esculetin not only restores mitochondrial dysfunction and structural changes but also alleviates asthmatic features.

Increased mitochondrial arginine metabolism supports bioenergetics in asthma

“…Stereologic quantitation of mitochondria in electron microscopy images performed in anonymized fashion also suggested a greater mitochondria volume in asthmatic bronchial epithelial cells (volume of mitochondria/volume of cell, control 0.10 ± 0.01, n = 5, asthma 0.13 ± 0.01, n = 4 subjects, P = 0.05, 1-tailed t test), i.e., asthmatic epithelium may have larger and/or more mitochondria. These findings of alterations in mitochondrial ultrastructure and/or numbers are consistent with prior observations in airways of an allergen-murine asthma model (36,37). ARG2 overexpression shifts metabolism to oxidative pathways and dampens the activation of proinflammatory signal transducers, HIFs, and STAT6.…”

Loss-of-function of inositol polyphosphate-4-phosphatase reversibly increases the severity of allergic airway inflammation

“…Airway resistance was determined using the flexiVent (Scireq, Canada) invasive airway mechanics system 46,47 . Briefly, each mouse was anaesthetized with xylazine and pentobarbital sodium, intubated after tracheotomy and ventilated.…”

“…BAL was performed and differential cell counts were estimated 46,47 . Briefly, BAL was performed with cold PBS, centrifuged, and scale bars equal 50 µm.…”

“…Immunohistochemistry was performed 47 using goat polyclonal INPP4A primary antibody (1:75, Santa Cruz Biotechnology, USA) as primary antibody and horseradish peroxidase-conjugated anti-goat IgG (Sigma Chemical Co.) as secondary antibody. Goat gamma globulins (Jackson Immunoresearch Laboratories, Inc., USA) were used as isotype controls in negative control experiments.…”

Mechanism and Effect of Esculetin in an Experimental Animal Model of Inflammatory Bowel Disease

“…In addition, it has been shown to inhibit the lipoxygenase and cyclooxygenase pathways of arachidonic acid metabolism (3)(4)(5), reduce the expression of matrix metalloproteinases (6,7) and downregulate the production of the cytokines IL-6 and IL-8 (8). As evidenced by both in vitro and in vivo studies, these properties can account for the different biological effects of this compound, including its ability to decrease liver neutrophil infiltration (9), attenuate sub-epithelial fibrosis and TGF-pi levels in the lung (10) and protect DNA against oxidative stress (4). All these effects clearly contribute to the different pharmacological activities of esculetin, including analgesic effects (11), anti-carcinogenic properties (12,13) and immunomodulatory functions (14).…”