PMID- 30639343
OWN - NLM
STAT- MEDLINE
DCOM- 20200608
LR  - 20240213
IS  - 1097-6825 (Electronic)
IS  - 0091-6749 (Print)
IS  - 0091-6749 (Linking)
VI  - 143
IP  - 6
DP  - 2019 Jun
TI  - Dysfunctional ErbB2, an EGF receptor family member, hinders repair of airway 
      epithelial cells from asthmatic patients.
PG  - 2075-2085.e10
LID - S0091-6749(19)30008-9 [pii]
LID - 10.1016/j.jaci.2018.11.046 [doi]
AB  - BACKGROUND: Genetic and genomic data increasingly point to the airway epithelium 
      as critical to asthma pathogenesis. Epithelial growth factor (EGF) family members 
      play a fundamental role in epithelial differentiation, proliferation, and repair. 
      Although expression of erythroblastosis oncogene B2 (ErbB2) mRNA, an EGF family 
      receptor, was reported to be lower in asthmatic patients, little is understood 
      about its functional role. OBJECTIVE: We sought to determine whether decreased 
      ErbB2 activation in freshly isolated human airway epithelial cells (HAECs) from 
      asthmatic patients associated with impaired wound closure in vitro. METHODS: An 
      in vitro scratch-wound model of air-liquid interface cultured and freshly 
      isolated HAECs were compared between HAECs from healthy control subjects (HCs) 
      and asthmatic patients in relation to ErbB2. RESULTS: Freshly brushed HAECs from 
      asthmatic patients had impaired ErbB2 activation compared with those from HCs. In 
      an in vitro scratch-wound model, HAECs from asthmatic patients showed delayed 
      wound closure compared with HAECs from HCs. Cell proliferation, as assessed based 
      on [(3)H] thymidine incorporation after wounding, and expression or activation of 
      ErbB2 and cyclin D1 at the leading edge of the wound were lower in HAECs from 
      asthmatic patients and HCs. A selective ErbB2 tyrosine kinase inhibitor, 
      mubritinib, impaired wound closure and decreased cyclin D1 expression in healthy 
      HAECs, with less effect on cells from asthmatic patients, supporting diminished 
      activity in asthmatic patients. CONCLUSION: These results implicate a primary 
      defect in the ErbB2 pathway as constraining epithelial repair processes in 
      asthmatic patients. Restoration of homeostatic ErbB2 function should be 
      considered a novel asthma therapeutic target.
CI  - Copyright (c) 2019. Published by Elsevier Inc.
FAU - Inoue, Hideki
AU  - Inoue H
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pa; Division of Pulmonary and 
      Allergy Medicine, Department of Medicine, Showa University School of Medicine, 
      Tokyo, Japan.
FAU - Hattori, Takeshi
AU  - Hattori T
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pa.
FAU - Zhou, Xiuxia
AU  - Zhou X
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pa.
FAU - Etling, Emily B
AU  - Etling EB
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pa.
FAU - Modena, Brian D
AU  - Modena BD
AD  - Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, Calif; 
      Department of Allergy, Asthma and Immunology, Scripps Health, San Diego, Calif.
FAU - Trudeau, John B
AU  - Trudeau JB
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pa.
FAU - Holguin, Fernando
AU  - Holguin F
AD  - Division of Medicine-Pulmonary Sciences & Critical Care, University of Colorado 
      School of Medicine, Aurora, Colo.
FAU - Wenzel, Sally E
AU  - Wenzel SE
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, University of Pittsburgh, Pittsburgh, Pa. Electronic address: 
      SWENZEL@pitt.edu.
LA  - eng
GR  - UL1 RR024153/RR/NCRR NIH HHS/United States
GR  - R01 HL069174/HL/NHLBI NIH HHS/United States
GR  - K23 HL144418/HL/NHLBI NIH HHS/United States
GR  - R01 HL064937/HL/NHLBI NIH HHS/United States
GR  - P01 AI106684/AI/NIAID NIH HHS/United States
GR  - R01 AI040600/AI/NIAID NIH HHS/United States
GR  - U10 HL109152/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190110
PL  - United States
TA  - J Allergy Clin Immunol
JT  - The Journal of allergy and clinical immunology
JID - 1275002
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
MH  - Adult
MH  - Asthma/*immunology/pathology
MH  - Cells, Cultured
MH  - Epithelial Cells/*immunology/pathology
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Receptor, ErbB-2/*immunology
MH  - Wound Healing
MH  - Young Adult
PMC - PMC6556416
MID - NIHMS1020874
OTO - NOTNLM
OT  - Asthma
OT  - air-liquid interface culture
OT  - airway inflammation
OT  - cell proliferation
OT  - cyclin D1
OT  - epidermal growth factor receptor
OT  - epithelial cell
OT  - erythroblastosis oncogene B2
OT  - wound repair
COIS- The authors have declared that no conflict of interest exists.
EDAT- 2019/01/15 06:00
MHDA- 2020/06/09 06:00
PMCR- 2019/06/09
CRDT- 2019/01/15 06:00
PHST- 2018/06/18 00:00 [received]
PHST- 2018/11/26 00:00 [revised]
PHST- 2018/11/30 00:00 [accepted]
PHST- 2019/01/15 06:00 [pubmed]
PHST- 2020/06/09 06:00 [medline]
PHST- 2019/01/15 06:00 [entrez]
PHST- 2019/06/09 00:00 [pmc-release]
AID - S0091-6749(19)30008-9 [pii]
AID - 10.1016/j.jaci.2018.11.046 [doi]
PST - ppublish
SO  - J Allergy Clin Immunol. 2019 Jun;143(6):2075-2085.e10. doi: 
      10.1016/j.jaci.2018.11.046. Epub 2019 Jan 10.