Premium
AIRWAY EPITHELIAL PHOSPHOINOSITIDE 3‐KINASE DELTA CONTRIBUTES TO THE MODULATION OF FUNGI‐INDUCED INNATE IMMUNE RESPONSE
Author(s) -
YONG CHUL LEE,
HAE JIN PARK,
KYUNG BAE LEE,
JAE JUN HEO,
SO RI KIM,
JAE SEOK JEONG,
KYUNG BAE,
LEE,
JONG HWAN WOO,
W S DANIEL TAN,
HONG YONG PEH,
TZE,
KHEE CHAN
Publication year - 2017
Publication title -
respirology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 85
eISSN - 1440-1843
pISSN - 1323-7799
DOI - 10.1111/resp.13206_198
Subject(s) - innate immune system , medicine , citation , airway , immune system , immunology , library science , computer science , surgery
Background and Aims: Under persistent stressful condition, the balance between fission and fusion of mitochondria is out of control. However, there is little information on mitochondrial dynamics and mitophagy in the pathogenesis of bronchial asthma. In this study, we aimed to evaluate the morphologic changes of mitochondria in cells from lung tissues of a murine model of fungus-induced bronchial asthma. Methods: Transmission electron microscopic (TEM) analysis was used to measure the mitochondrial dynamics in lung of fungal allergen inhaled mice. Results: The mice sensitized and challenged with Aspergillus fumigatus (Af-exposed mice) showed the typical features of bronchial asthma. 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, TEM analysis revealed that in lung cells from Af-exposed mice, the mitochondria were dramatically elongated and 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. We also found that the levels of the mitochondrial fission related protein and mitophagy related indicators were increased in Af-exposed mice. Conclusions: These findings indicate that the mitochondrial hyperfusion can be induced by fungal allergen stimulation in lung cells and it may be one of the molecular mechanisms for the pathogenesis of steroidresistant allergic airway inflammation.