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* Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi, India; and
Division of Renal Pathology, Department of Pathology and
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 The study was funded by the Network Project (NWP0033) of the Council of Scientific and Industrial Research, Government of India. U.M. acknowledges the Indian Council of Medical Research for his fellowship.
2 Address correspondence and reprint requests to Dr. Balaram Ghosh, Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Mall Road, Delhi-110007, India. E-mail address: bghosh{at}igib.res.in
3 Abbreviations used in this paper: LOX, lipoxygenase; AHR, airway hyperresponsiveness; COXETC, cytochrome c oxidase of electron transport chain; CYTO, cytosolic fraction; ESC, esculetin; HODE, hydroxyoctadecaenoic acid; HETE, hydroxyeicosatetraenoic acid; L-OOH, lipid hydroperoxide; LOX, lipoxygenase; Penh, enhanced pause; sGAW, specific airway conductance; sRAW, specific airway resistance; VEH, vehicle; MCh, methacholine; SHAM, saline sensitized.
This article has been cited by other articles:
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  U. Mabalirajan, A. Agrawal, and B. Ghosh Comment on "Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation" J. Immunol., November 15, 2009; 183(10): 6039 - 6039. [Full Text] [PDF]
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D. C. Webb Response to Comment on "Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenaes: Identification of a Novel Pathway for Regulating Allergic Inflammation" J. Immunol., November 15, 2009; 183(10): 6039 - 6040. [Full Text] [PDF]
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 U. Mabalirajan, J. Aich, G. D. Leishangthem, S. K. Sharma, A. K. Dinda, and B. Ghosh Effects of vitamin E on mitochondrial dysfunction and asthma features in an experimental allergic murine model J Appl Physiol, October 1, 2009; 107(4): 1285 - 1292. [Abstract] [Full Text] [PDF]
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