title: Protein disulfide isomerase-endoplasmic reticulum resident protein 57 regulates allergen-induced airways inflammation, fibrosis, and hyperresponsiveness.
abstract: BACKGROUND
  Evidence for association between asthma and the unfolded protein response is emerging. Endoplasmic reticulum resident protein 57 (ERp57) is an endoplasmic reticulum-localized redox chaperone involved in folding and secretion of glycoproteins. We have previously demonstrated that ERp57 is upregulated in allergen-challenged human and murine lung epithelial cells. However, the role of ERp57 in asthma pathophysiology is unknown.
  
  
  OBJECTIVE
  Here we sought to examine the contribution of airway epithelium-specific ERp57 in the pathogenesis of allergic asthma.
  
  
  METHODS
  We examined the expression of ERp57 in human asthmatic airway epithelium and used murine models of allergic asthma to evaluate the relevance of epithelium-specific ERp57.
  
  
  RESULTS
  Lung biopsy specimens from asthmatic and nonasthmatic patients revealed a predominant increase in ERp57 levels in epithelium of asthmatic patients. Deletion of ERp57 resulted in a significant decrease in inflammatory cell counts and airways resistance in a murine model of allergic asthma. Furthermore, we observed that disulfide bridges in eotaxin, epidermal growth factor, and periostin were also decreased in the lungs of house dust mite-challenged ERp57-deleted mice. Fibrotic markers, such as collagen and α smooth muscle actin, were also significantly decreased in the lungs of ERp57-deleted mice. Furthermore, adaptive immune responses were dispensable for house dust mite-induced endoplasmic reticulum stress and airways fibrosis.
  
  
  CONCLUSIONS
  Here we show that ERp57 levels are increased in the airway epithelium of asthmatic patients and in mice with allergic airways disease. The ERp57 level increase is associated with redox modification of proinflammatory, apoptotic, and fibrotic mediators and contributes to airways hyperresponsiveness. The strategies to inhibit ERp57 specifically within the airways epithelium might provide an opportunity to alleviate the allergic asthma phenotype.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Sidra M
authors.initials: SM
authors.lastname: Hoffman
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT; Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Chapman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Karolyn G
authors.initials: KG
authors.lastname: Lahue
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT.
authors.forename: Jonathon M
authors.initials: JM
authors.lastname: Cahoon
authors.affiliation: Department of Biology, University of Vermont, Burlington, VT.
authors.forename: Gurkiranjit K
authors.initials: GK
authors.lastname: Rattu
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Nirav
authors.initials: N
authors.lastname: Daphtary
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Minara
authors.initials: M
authors.lastname: Aliyeva
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Fortner
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Suzy A A
authors.initials: SA
authors.lastname: Comhair
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.affiliation: Department of Medicine, University of California, San Francisco, Calif.
authors.forename: Nirav
authors.initials: N
authors.lastname: Bhakta
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Dixon
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Irvin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
authors.affiliation: Department of Medicine, University of Vermont College of Medicine, Burlington, VT.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Poynter
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT. Electronic address: Vikas.anathy@med.uvm.edu.
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001706:Biopsy; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D000485:Allergens; D016207:Cytokines; D050998:bcl-2 Homologous Antagonist-Killer Protein; D053148:Caspase 3; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human
keywords: Unfolded protein response; airways hyperresponsiveness; asthma; endoplasmic reticulum protein 57; endoplasmic reticulum stress; epithelium; house dust mite; protein disulfide isomerase; recombination-activating gene 1