PMID- 21169555
OWN - NLM
STAT- MEDLINE
DCOM- 20111108
LR  - 20220414
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 45
IP  - 3
DP  - 2011 Sep
TI  - Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of 
      alveolar epithelial cells: effects of misfolded surfactant protein.
PG  - 498-509
LID - 10.1165/rcmb.2010-0347OC [doi]
AB  - Endoplasmic reticulum (ER) stress has been implicated in alveolar epithelial type 
      II (AT2) cell apoptosis in idiopathic pulmonary fibrosis. We hypothesized that ER 
      stress (either chemically induced or due to accumulation of misfolded proteins) 
      is also associated with epithelial-mesenchymal transition (EMT) in alveolar 
      epithelial cells (AECs). ER stress inducers, thapsigargin (TG) or tunicamycin 
      (TN), increased expression of ER chaperone, Grp78, and spliced X-box binding 
      protein 1, decreased epithelial markers, E-cadherin and zonula occludens-1 
      (ZO-1), increased the myofibroblast marker, alpha-smooth muscle actin (alpha-SMA), and 
      induced fibroblast-like morphology in both primary AECs and the AT2 cell line, 
      RLE-6TN, consistent with EMT. Overexpression of the surfactant protein (SP)-C 
      BRICHOS mutant SP-C(DeltaExon4) in A549 cells increased Grp78 and alpha-SMA and disrupted 
      ZO-1 distribution, and, in primary AECs, SP-C(DeltaExon4) induced fibroblastic-like 
      morphology, decreased ZO-1 and E-cadherin and increased alpha-SMA, mechanistically 
      linking ER stress associated with mutant SP to fibrosis through EMT. Whereas EMT 
      was evident at lower concentrations of TG or TN, higher concentrations caused 
      apoptosis. The Src inhibitor, 
      4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4]pyramidine) (PP2), abrogated 
      EMT associated with TN or TG in primary AECs, whereas overexpression of 
      SP-C(DeltaExon4) increased Src phosphorylation, suggesting a common mechanism. 
      Furthermore, increased Grp78 immunoreactivity was observed in AT2 cells of mice 
      after bleomycin injury, supporting a role for ER stress in epithelial 
      abnormalities in fibrosis in vivo. These results demonstrate that ER stress 
      induces EMT in AECs, at least in part through Src-dependent pathways, suggesting 
      a novel role for ER stress in fibroblast accumulation in pulmonary fibrosis.
FAU - Zhong, Qian
AU  - Zhong Q
AD  - Will Rogers Institute Pulmonary Research Center, Division of Pulmonary and 
      Critical Care Medicine, Department of Medicine, University of Southern 
      California, Keck School of Medicine, Los Angeles, CA 90033, USA.
FAU - Zhou, Beiyun
AU  - Zhou B
FAU - Ann, David K
AU  - Ann DK
FAU - Minoo, Parviz
AU  - Minoo P
FAU - Liu, Yixin
AU  - Liu Y
FAU - Banfalvi, Agnes
AU  - Banfalvi A
FAU - Krishnaveni, Manda S
AU  - Krishnaveni MS
FAU - Dubourd, Mickael
AU  - Dubourd M
FAU - Demaio, Lucas
AU  - Demaio L
FAU - Willis, Brigham C
AU  - Willis BC
FAU - Kim, Kwang-Jin
AU  - Kim KJ
FAU - duBois, Roland M
AU  - duBois RM
FAU - Crandall, Edward D
AU  - Crandall ED
FAU - Beers, Michael F
AU  - Beers MF
FAU - Borok, Zea
AU  - Borok Z
LA  - eng
GR  - DE014183/DE/NIDCR NIH HHS/United States
GR  - R01 HL062569/HL/NHLBI NIH HHS/United States
GR  - HL038621/HL/NHLBI NIH HHS/United States
GR  - R01 HL089445/HL/NHLBI NIH HHS/United States
GR  - R01 HL038621/HL/NHLBI NIH HHS/United States
GR  - R01 ES017034/ES/NIEHS NIH HHS/United States
GR  - HL062569/HL/NHLBI NIH HHS/United States
GR  - R01 HL095349/HL/NHLBI NIH HHS/United States
GR  - R37 HL062569/HL/NHLBI NIH HHS/United States
GR  - RC2 ES018782/ES/NIEHS NIH HHS/United States
GR  - ES018782/ES/NIEHS NIH HHS/United States
GR  - R01 DE014183/DE/NIDCR NIH HHS/United States
GR  - HL019737/HL/NHLBI NIH HHS/United States
GR  - R01 HL038578/HL/NHLBI NIH HHS/United States
GR  - HL089445/HL/NHLBI NIH HHS/United States
GR  - DE010742/DE/NIDCR NIH HHS/United States
GR  - HL056590/HL/NHLBI NIH HHS/United States
GR  - P01 HL019737/HL/NHLBI NIH HHS/United States
GR  - HL095349/HL/NHLBI NIH HHS/United States
GR  - R01 DE010742/DE/NIDCR NIH HHS/United States
GR  - R01 HL056590/HL/NHLBI NIH HHS/United States
GR  - HL038578/HL/NHLBI NIH HHS/United States
GR  - ES017034/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101217
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (Hspa5 protein, mouse)
RN  - 0 (Pulmonary Surfactant-Associated Protein C)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Endoplasmic Reticulum/*metabolism
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Epithelium/*pathology
MH  - Fibroblasts/metabolism
MH  - *Gene Expression Regulation
MH  - Humans
MH  - Male
MH  - Mesoderm/*pathology
MH  - Mice
MH  - Mutation
MH  - Protein Denaturation
MH  - Pulmonary Alveoli/*metabolism
MH  - Pulmonary Fibrosis/metabolism
MH  - Pulmonary Surfactant-Associated Protein C/*chemistry
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC3175581
EDAT- 2010/12/21 06:00
MHDA- 2011/11/09 06:00
PMCR- 2012/09/01
CRDT- 2010/12/21 06:00
PHST- 2010/12/21 06:00 [entrez]
PHST- 2010/12/21 06:00 [pubmed]
PHST- 2011/11/09 06:00 [medline]
PHST- 2012/09/01 00:00 [pmc-release]
AID - 2010-0347OC [pii]
AID - 10.1165/rcmb.2010-0347OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2011 Sep;45(3):498-509. doi: 10.1165/rcmb.2010-0347OC. 
      Epub 2010 Dec 17.