title: Cigarette Smoke Induces Human Epidermal Receptor 2-Dependent Changes in Epithelial Permeability.
abstract: The airway epithelium constitutes a protective barrier against inhaled insults, such as viruses, bacteria, and toxic fumes, including cigarette smoke (CS). Maintenance of bronchial epithelial integrity is central for airway health, and defective epithelial barrier function contributes to the pathogenesis of CS-mediated diseases, such as chronic obstructive pulmonary disease. Although CS has been shown to increase epithelial permeability, current understanding of the mechanisms involved in CS-induced epithelial barrier disruption remains incomplete. We have previously identified that the receptor tyrosine kinase human epidermal receptor (HER) 2 growth factor is activated by the ligand neuregulin-1 and increases epithelial permeability in models of inflammatory acute lung injury. We hypothesized that CS activates HER2 and that CS-mediated changes in barrier function would be HER2 dependent in airway epithelial cells. We determined that HER2 was activated in whole lung, as well as isolated epithelial cells, from smokers, and that acute CS exposure resulted in HER2 activation in cultured bronchial epithelial cells. Mechanistic studies determined that CS-mediated HER2 activation is independent of neuregulin-1 but required upstream activation of the epidermal growth factor receptor. HER2 was required for CS-induced epithelial permeability as knockdown of HER2 blocked increases in permeability after CS. CS caused an increase in IL-6 production by epithelial cells that was dependent on HER2-mediated extracellular signal-regulated kinases (Erk) activation. Finally, blockade of IL-6 attenuated CS-induced epithelial permeability. Our data indicate that CS activates pulmonary epithelial HER2 and that HER2 is a central mediator of CS-induced epithelial barrier dysfunction.
authors.affiliation: 1 Division Oncology, National Jewish Health, Denver, Colorado.
authors.forename: Rangnath
authors.initials: R
authors.lastname: Mishra
authors.affiliation: 1 Division Oncology, National Jewish Health, Denver, Colorado.
authors.forename: Daniel
authors.initials: D
authors.lastname: Foster
authors.affiliation: 1 Division Oncology, National Jewish Health, Denver, Colorado.
authors.forename: Vihas T
authors.initials: VT
authors.lastname: Vasu
authors.affiliation: 1 Division Oncology, National Jewish Health, Denver, Colorado.
authors.forename: Jyoti V
authors.initials: JV
authors.lastname: Thaikoottathil
authors.affiliation: 2 Division Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado; and.|3 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado.
authors.forename: Beata
authors.initials: B
authors.lastname: Kosmider
authors.affiliation: 2 Division Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado; and.|3 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
authors.affiliation: 2 Division Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado; and.|3 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
authors.affiliation: 1 Division Oncology, National Jewish Health, Denver, Colorado.|2 Division Pulmonary and Critical Care Medicine, National Jewish Health, Denver, Colorado; and.|3 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver, Colorado.
authors.forename: James H
authors.initials: JH
authors.lastname: Finigan
mesh_terms: D000818:Animals; D002460:Cell Line; D002463:Cell Membrane Permeability; D017097:Electric Impedance; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008810:Mice, Inbred C57BL; D020890:Neuregulin-1 / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects*
chemical_list: D066246:ErbB Receptors; D015850:Interleukin-6; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human
keywords: cigarette smoke; epidermal growth factor receptor; human epidermal receptor 2; permeability; pulmonary epithelium