Background: The endoplasmic reticulum (ER) stress response participates in many chronic inflammatory and\r\nautoimmune diseases. In the current study, we sought to examine the contribution of ER stress transducers in the\r\npathogenesis of three principal facets of allergic asthma: inflammation, airway fibrosis, and airways\r\nhyperresponsiveness.\r\nMethods: House Dust Mite (HDM) was used as an allergen for in vitro and in vivo challenge of primary human and\r\nmurine airway epithelial cells. ER stress transducers were modulated using specific small interfering RNAs (siRNAs)\r\nin vivo. Inflammation, airway remodeling, and hyperresponsiveness were measured by total bronchoalveolar lavage\r\n(BAL) cell counts, determination of collagen, and methacholine responsiveness in mice, respectively.\r\nResults: Challenge of human bronchiolar and nasal epithelial cells with HDM extract induced the ER stress\r\ntransducer, activating transcription factor 6 a (ATF6a) as well as protein disulfide isomerase, ERp57, in association\r\nwith activation of caspase-3. SiRNA-mediated knockdown of ATF6a and ERp57 during HDM administration in mice\r\nresulted in a decrease in components of HDM-induced ER stress, disulfide mediated oligomerization of Bak, and\r\nactivation of caspase-3. Furthermore, siRNA-mediated knockdown of ATF6a and ERp57 led to decreased\r\ninflammation, airway hyperresponsiveness and airway fibrosis.\r\nConclusion: Collectively, our work indicates that HDM induces ER stress in airway epithelial cells and that ATF6a\r\nand ERp57 play a significant role in the development of cardinal features of allergic airways disease. Inhibition of ER\r\nstress responses may provide a potential therapeutic avenue in chronic asthma and sub-epithelial fibrosis associated\r\nwith loss of lung function.
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