Friday, 16 October 2015
Hall D1 Foyer (Floor 3) (Coex Convention Center)
Subcellular organelles including mitochondria are now considered as one major target for many therapeutic approaches. Each subcellular organelle seems to have uncanonical actions implicated in various inflammatory/immune responses as well as classic functions to maintain the cell fate physiologically. In fact, under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defined as ER stress which has been reported to be involved in the inflammatory component of chronic diseases including bronchial asthma. The NLRP3 inflammasome is a molecular platform activated upon signs of cellular ‘danger’ to trigger innate immune defenses. Moreover, association between NLRP3 and mitochondria comes from the observation that activated NLRP3 appears to traffic from the ER to perinuclear areas similarly to mitochondria-associated ER membranes (MAMs). In this study, we investigated whether the allergen-induced cellular stress evokes the conformational association between ER and mitochondria in the airway inflammatory cells and which are involved in the pathogenesis of bronchial asthma using confocal and electron-microscopic analysis with various molecular biological analytic methods. The mice sensitized with OVA and LPS and then challenged with OVA (OVALPS-OVA mice) mice showed the typical features of neutrophilic asthma; increased airway inflammatory cells, the pathologic changes, the increased levels of Th2 cytokines in lungs of OVALPS-OVA mice, increased the expression of ER stress markers and NLRP3, and increased bronchial hyperresponsiveness. Interestingly, confocal analysis and electron-microscopic findings revealed that in BAL cells from OVALPS-OVA mice, the ER and mitochondria get closed each other even seemed to be united one compared to the finding of cells from control mice. 4-PBA, an ER stress regulator significantly reduced the increases in inflammatory cytokines, mitochondrial ROS generation, airway inflammation, and bronchial hyperresponsiveness. These findings indicate that the development of ER-mitochondria complex induced by ER stress in airway inflammatory cells may be implicated in the pathogenesis of bronchial asthma, providing the novel therapeutic target for bronchial asthma.