PMID- 24092566
OWN - NLM
STAT- MEDLINE
DCOM- 20140428
LR  - 20211021
IS  - 1468-3296 (Electronic)
IS  - 0040-6376 (Print)
IS  - 0040-6376 (Linking)
VI  - 69
IP  - 3
DP  - 2014 Mar
TI  - Increased ectodomain shedding of lung epithelial cell adhesion molecule 1 as a 
      cause of increased alveolar cell apoptosis in emphysema.
PG  - 223-31
LID - 10.1136/thoraxjnl-2013-203867 [doi]
AB  - RATIONALE: Alveolar epithelial cell apoptosis and protease/antiprotease imbalance 
      based proteolysis play central roles in the pathogenesis of pulmonary emphysema 
      but molecular mechanisms underlying these two events are not yet clearly 
      understood. Cell adhesion molecule 1 (CADM1) is a lung epithelial cell adhesion 
      molecule in the immunoglobulin superfamily. It generates two membrane associated 
      C terminal fragments (CTFs), alphaCTF and betaCTF, through protease mediated ectodomain 
      shedding. OBJECTIVE: To explore the hypothesis that more CADM1-CTFs are generated 
      in emphysematous lungs through enhanced ectodomain shedding, and cause increased 
      apoptosis of alveolar epithelial cells. METHODS AND RESULTS: Western blot 
      analyses revealed that CADM1-CTFs increased in human emphysematous lungs in 
      association with increased ectodomain shedding. Increased apoptosis of alveolar 
      epithelial cells in emphysematous lungs was confirmed by terminal nucleotide nick 
      end labelling (TUNEL) assays. NCI-H441 lung epithelial cells expressing mature 
      CADM1 but not CTFs were induced to express alphaCTF both endogenously (by shedding 
      inducers phorbol ester and trypsin) and exogenously (by transfection). Cell 
      fractionation, immunofluorescence, mitochondrial membrane potentiometric JC-1 dye 
      labelling and TUNEL assays revealed that CADM1-alphaCTF was localised to mitochondria 
      where it decreased mitochondrial membrane potential and increased cell apoptosis. 
      A mutation in the intracytoplasmic domain abrogated all three abilities of alphaCTF. 
      CONCLUSIONS: CADM1 ectodomain shedding appeared to cause alveolar cell apoptosis 
      in emphysematous lungs by producing alphaCTF that accumulated in mitochondria. These 
      data link proteolysis to apoptosis, which are two landmark events in emphysema.
FAU - Mimae, Takahiro
AU  - Mimae T
AD  - Department of Surgical Oncology, Research Institute for Radiation Biology and 
      Medicine, Graduate School of Biomedical Sciences, Hiroshima University, , 
      Hiroshima, Japan.
FAU - Hagiyama, Man
AU  - Hagiyama M
FAU - Inoue, Takao
AU  - Inoue T
FAU - Yoneshige, Azusa
AU  - Yoneshige A
FAU - Kato, Takashi
AU  - Kato T
FAU - Okada, Morihito
AU  - Okada M
FAU - Murakami, Yoshinori
AU  - Murakami Y
FAU - Ito, Akihiko
AU  - Ito A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131002
PL  - England
TA  - Thorax
JT  - Thorax
JID - 0417353
RN  - 0 (Biomarkers)
RN  - 0 (CADM1 protein, human)
RN  - 0 (Cell Adhesion Molecule-1)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Immunoglobulin Fragments)
RN  - 0 (Immunoglobulins)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
SB  - IM
MH  - Alveolar Epithelial Cells/*metabolism/pathology
MH  - Apoptosis/*immunology
MH  - Biomarkers/metabolism
MH  - Blotting, Western
MH  - Cell Adhesion Molecule-1
MH  - Cell Adhesion Molecules/immunology/*metabolism
MH  - Humans
MH  - Immunoglobulin Fragments/*metabolism
MH  - Immunoglobulins/immunology/*metabolism
MH  - In Situ Nick-End Labeling
MH  - Intercellular Adhesion Molecule-1/metabolism
MH  - Predictive Value of Tests
MH  - Proteolysis
MH  - Pulmonary Emphysema/*genetics/immunology/*pathology
MH  - Risk Factors
MH  - Sensitivity and Specificity
MH  - Severity of Illness Index
MH  - Smoking/adverse effects
PMC - PMC3933066
OTO - NOTNLM
OT  - Airway Epithelium
OT  - Emphysema
EDAT- 2013/10/05 06:00
MHDA- 2014/04/29 06:00
PMCR- 2014/02/24
CRDT- 2013/10/05 06:00
PHST- 2013/10/05 06:00 [entrez]
PHST- 2013/10/05 06:00 [pubmed]
PHST- 2014/04/29 06:00 [medline]
PHST- 2014/02/24 00:00 [pmc-release]
AID - thoraxjnl-2013-203867 [pii]
AID - 10.1136/thoraxjnl-2013-203867 [doi]
PST - ppublish
SO  - Thorax. 2014 Mar;69(3):223-31. doi: 10.1136/thoraxjnl-2013-203867. Epub 2013 Oct 
      2.