title: Endoplasmic reticulum stress mediates house dust mite-induced airway epithelial apoptosis and fibrosis.
abstract: BACKGROUND
  The endoplasmic reticulum (ER) stress response participates in many chronic inflammatory and autoimmune diseases. In the current study, we sought to examine the contribution of ER stress transducers in the pathogenesis of three principal facets of allergic asthma: inflammation, airway fibrosis, and airways hyperresponsiveness.
  
  
  METHODS
  House Dust Mite (HDM) was used as an allergen for in vitro and in vivo challenge of primary human and murine airway epithelial cells. ER stress transducers were modulated using specific small interfering RNAs (siRNAs) in vivo. Inflammation, airway remodeling, and hyperresponsiveness were measured by total bronchoalveolar lavage (BAL) cell counts, determination of collagen, and methacholine responsiveness in mice, respectively.
  
  
  RESULTS
  Challenge of human bronchiolar and nasal epithelial cells with HDM extract induced the ER stress transducer, activating transcription factor 6 α (ATF6α) as well as protein disulfide isomerase, ERp57, in association with activation of caspase-3. SiRNA-mediated knockdown of ATF6α and ERp57 during HDM administration in mice resulted in a decrease in components of HDM-induced ER stress, disulfide mediated oligomerization of Bak, and activation of caspase-3. Furthermore, siRNA-mediated knockdown of ATF6α and ERp57 led to decreased inflammation, airway hyperresponsiveness and airway fibrosis.
  
  
  CONCLUSIONS
  Collectively, our work indicates that HDM induces ER stress in airway epithelial cells and that ATF6α and ERp57 play a significant role in the development of cardinal features of allergic airways disease. Inhibition of ER stress responses may provide a potential therapeutic avenue in chronic asthma and sub-epithelial fibrosis associated with loss of lung function.
authors.forename: Sidra M
authors.initials: SM
authors.lastname: Hoffman
authors.forename: Jane E
authors.initials: JE
authors.lastname: Tully
authors.forename: James D
authors.initials: JD
authors.lastname: Nolin
authors.forename: Karolyn G
authors.initials: KG
authors.lastname: Lahue
authors.forename: Dylan H
authors.initials: DH
authors.lastname: Goldman
authors.forename: Nirav
authors.initials: N
authors.lastname: Daphtary
authors.forename: Minara
authors.initials: M
authors.lastname: Aliyeva
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.forename: Anne E
authors.initials: AE
authors.lastname: Dixon
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.affiliation: Department of Pathology, Vermont Lung Center University of Vermont College of Medicine, Burlington, VT 05405, USA. vikas.anathy@med.uvm.edu.
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
mesh_terms: D051702:Activating Transcription Factor 6 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001980:Bronchi / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D016210:Methacholine Chloride / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D019704:Protein Disulfide-Isomerases / Q000172:deficiency / Q000187:drug effects / Q000235:genetics; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D039981:Pyroglyphidae / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D034741:RNA, Small Interfering; D016210:Methacholine Chloride; D003094:Collagen; D053148:Caspase 3; C513195:Pdia3 protein, mouse; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human