부산대학교 도서관

Rationale: Mitochondria are dynamic organelles that undergo fission and fusion events, but we are only beginning to understand some of the reasons and the machineries involved in these processes. Recent studies have demonstrated that under persistent stressful condition, that is, pathologic condition, the balance between fission and fusion of mitochondria is out of control. However, there is little information on mitochondrial dynamics in the pathogenesis of bronchial asthma, especially fungus-induced allergic airway inflammation.Methods: In this study, we have evaluated the morphologic changes of mitochondria in cells from lung tissues of a murine model of fungus-induced bronchial asthma.Results: The mice sensitized and challenged with Aspergillus fumigatus (Af-exposed mice) showed the typical features of bronchial asthma; increased airway inflammatory cells, the pathologic changes, the increased levels of Th2 cytokines and epithelial cell derived cytokines in lungs of Af-exposed mice, and increased bronchial hyper-responsiveness. Interestingly, these asthmatic features were refractory to the treatment with oral dexamethasone, whereas they were improved significantly by the administration of mitochondrial reactive oxygen species (ROS) inhibitor, NecroX-7. In addition, electron-microscopic analysis revealed that in lung cells from Af-exposed mice, the mitochondria were dramatically elongated, fused each other compared to the finding in cells from control mice. The levels of mitofusin (Mfn)-1 and Mfn-2, mitochondrial fusion proteins, were significantly increased in BAL cells, primary cultured tracheal epithelial cells, and lung tissues of Af-exposed mice. The increases in Mfn-1 and Mfn-2 levels and morphological changes did not respond to oral dexamethasone, but NecroX-7 decreased the expression of mitofusins and restored the morphology of mitochondria. We also found that in vivo administration of siRNA targeting Mfn-2 modestly improved the asthmatic manifestations and mitochondrial dynamics in Af-exposed mice.Conclusion: These findings indicate that the mitochondrial hyper-fusion may be induced by fungal allergen stimulation in lung cells and it may be one of the molecular mechanisms for the pathogenesis of steroid-resistant allergic airway inflammation.