PMID- 31173170
OWN - NLM
STAT- MEDLINE
DCOM- 20191223
LR  - 20200225
IS  - 1791-244X (Electronic)
IS  - 1107-3756 (Print)
IS  - 1107-3756 (Linking)
VI  - 44
IP  - 2
DP  - 2019 Aug
TI  - Investigating the regulatory role of ORMDL3 in airway barrier dysfunction using 
      in vivo and in vitro models.
PG  - 535-548
LID - 10.3892/ijmm.2019.4233 [doi]
AB  - The airway epithelium (AE) is the main protective barrier between the host and 
      external environmental factors causing asthma. Allergens or pathogens induce AE 
      dysfunction, including epithelial permeability alteration, trans‑epithelial 
      electrical resistance (TEER) reduction, upregulation of inflammatory mediators 
      and downregulation of junctional complex molecules. Orosomucoid‑like protein 
      isoform 3 (ORMDL3), a gene closely associated with childhood onset asthma, is 
      involved in airway inflammation and remodeling. It was hypothesized that ORMDL3 
      plays an important role in regulating AE barrier function. In vivo [chronic 
      asthma induced by ovalbumin‑respiratory syncytial virus (OVA‑RSV)] in mice) and 
      in vitro (human bronchial epithelial cells and 16HBE cells) models were used to 
      assess ORMDL3's role in AE function regulation, evaluating paracellular 
      permeability, TEER and the expression levels of junctional complex molecules. The 
      effects of ORMDL3 on the extracellular signal‑regulated protein kinase (ERK) 
      pathway were determined. In mice with OVA‑RSV induced chronic asthma, ORMDL3 and 
      sphingosine kinase 1 (SPHK1) were upregulated whereas the junction related 
      proteins Claudin‑18 and E‑cadherin were downregulated. Overexpression of ORMDL3 
      resulted in decreased TEER, downregulation of junctional complex molecules and 
      induced epithelial permeability. In contrast, ORMDL3 inhibition showed the 
      opposite effects. In 16HBE cells, ORMDL3 overexpression induced SPHK1 
      distribution and activity, while SPHK1 inhibition resulted in increased TEER upon 
      administration of an ORMDL3 agonist or ORMDL3 overexpression. In addition, ERK 
      activation occurred downstream of SPHK1 activation in 16HBE cells. High levels of 
      ORMDL3 result in damaged AE barrier function by inducing the SPHK1/ERK pathway.
FAU - Yang, Ruixue
AU  - Yang R
AD  - Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.
FAU - Tan, Min
AU  - Tan M
AD  - Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.
FAU - Xu, Jianya
AU  - Xu J
AD  - Jiangsu Key Laboratory of Pediatric Respiratory Disease, Nanjing, Jiangsu 210023, 
      P.R. China.
FAU - Zhao, Xia
AU  - Zhao X
AD  - Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20190606
PL  - Greece
TA  - Int J Mol Med
JT  - International journal of molecular medicine
JID - 9810955
RN  - 0 (Membrane Proteins)
RN  - 0 (ORMDL3 protein, human)
RN  - 0 (ORMDL3 protein, mouse)
SB  - IM
MH  - Animals
MH  - Asthma/immunology/*pathology
MH  - Cell Line
MH  - Female
MH  - Humans
MH  - Lung/immunology/pathology
MH  - Membrane Proteins/*analysis/immunology
MH  - Mice, Inbred BALB C
MH  - Respiratory Mucosa/immunology/*pathology
PMC - PMC6605285
EDAT- 2019/06/08 06:00
MHDA- 2019/12/24 06:00
PMCR- 2019/06/06
CRDT- 2019/06/08 06:00
PHST- 2018/12/14 00:00 [received]
PHST- 2019/06/04 00:00 [accepted]
PHST- 2019/06/08 06:00 [pubmed]
PHST- 2019/12/24 06:00 [medline]
PHST- 2019/06/08 06:00 [entrez]
PHST- 2019/06/06 00:00 [pmc-release]
AID - ijmm-44-02-0535 [pii]
AID - 10.3892/ijmm.2019.4233 [doi]
PST - ppublish
SO  - Int J Mol Med. 2019 Aug;44(2):535-548. doi: 10.3892/ijmm.2019.4233. Epub 2019 Jun 
      6.