title: Reversal of cigarette smoke extract-induced sinonasal epithelial cell barrier dysfunction through Nrf2 Activation.
abstract: Environmental factors such as inhaled pollutants like cigarette smoke may play a significant role in diseases of the upper airway including chronic rhinosinusitis (CRS). Recent studies have shown that cigarette smoke causes impaired airway epithelial cell barrier function likely through environmental oxidative stress related pathways. The purpose of this study is to explore whether enhancing nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2], the body's master antioxidant system, can ameliorate cigarette smoke-induced sinonasal epithelial cell (SNEC) barrier dysfunction.
  
  
  
  Human SNECs (HSNECs) were grown from control patients at the air-liquid interface (ALI). HSNECs were stimulated with cigarette smoke extract (CSE) with and without pharmacologic activation of Nrf2. HSNECs were then stained for the epithelial cell junctional proteins zonula occludens 1 (ZO-1) and junctional adhesion molecule A (JAM-A) using confocal microscopy. In addition, transepithelial electrical resistance (TER) was measured in cultures before and after stimulation with CSE.
  
  
  
  CSE stimulation caused a global disruption of the epithelial junctional proteins ZO-1 and JAM-A along with an associated decrease in TER levels. Enhancing Nrf2 levels prior to stimulation with CSE was associated with increased localization of ZO-1 and JAM-A levels at the cell surface and statistically significant increases in TER levels.
  
  
  
  This is the first study to demonstrate that cigarette smoke induced SNEC barrier dysfunction is reversible by Nrf2 activation. The Nrf2 antioxidant pathway may represent a potential therapeutic target for cigarette smoke-associated sinonasal inflammation.
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors: Anuj
authors: A
authors: Tharakan
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors: Ashleigh A
authors: AA
authors: Halderman
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.
authors: Andrew P
authors: AP
authors: Lane
authors: Department of Environmental Health Sciences, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors: Shyam
authors: S
authors: Biswal
authors: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD. mramana3@jhmi.edu.
authors: Murugappan
authors: M
authors: Ramanathan
mesh_terms: D000328:Adult; D000368:Aged; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D005005:Ethmoid Sinus / Q000601:surgery; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism; D012906:Smoke; D014026:Nicotiana; D051195:Toll-Like Receptor 2 / Q000235:genetics; D055815:Young Adult; D062826:Zonula Occludens-1 Protein / Q000378:metabolism; D023083:beta-Defensins / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; C406407:DEFB1 protein, human; C407243:F11R protein, human; D018950:Lipopolysaccharide Receptors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012906:Smoke; C569042:TJP1 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D062826:Zonula Occludens-1 Protein; D023083:beta-Defensins
keywords: Nrf2; chronic rhinosinusitis; cigarette smoke; epithelial barrier; sinonasal epithelium; tight junctions