PMID- 32023086
OWN - NLM
STAT- MEDLINE
DCOM- 20200817
LR  - 20211030
IS  - 1535-4970 (Electronic)
IS  - 1073-449X (Print)
IS  - 1073-449X (Linking)
VI  - 201
IP  - 10
DP  - 2020 May 15
TI  - Hyperoxia Injury in the Developing Lung Is Mediated by Mesenchymal Expression of 
      Wnt5A.
PG  - 1249-1262
LID - 10.1164/rccm.201908-1513OC [doi]
AB  - Rationale: Bronchopulmonary dysplasia (BPD) is a leading complication of preterm 
      birth that affects infants born in the saccular stage of lung development at <32 
      weeks of gestation. Although the mechanisms driving BPD remain uncertain, 
      exposure to hyperoxia is thought to contribute to disease 
      pathogenesis.Objectives: To determine the effects of hyperoxia on 
      epithelial-mesenchymal interactions and to define the mediators of activated 
      Wnt/beta-catenin signaling after hyperoxia injury.Methods: Three hyperoxia models 
      were used: A three-dimensional organotypic coculture using primary human lung 
      cells, precision-cut lung slices (PCLS), and a murine in vivo hyperoxia model. 
      Comparisons of normoxia- and hyperoxia-exposed samples were made by real-time 
      quantitative PCR, RNA in situ hybridization, quantitative confocal microscopy, 
      and lung morphometry.Measurements and Main Results: Examination of an array of 
      Wnt ligands in the three-dimensional organotypic coculture revealed increased 
      mesenchymal expression of WNT5A. Inhibition of Wnt5A abrogated the BPD 
      transcriptomic phenotype induced by hyperoxia. In the PCLS model, Wnt5A 
      inhibition improved alveolarization following hyperoxia exposure, and treatment 
      with recombinant Wnt5a reproduced features of the BPD phenotype in PCLS cultured 
      in normoxic conditions. Chemical inhibition of NF-kappaB with BAY11-7082 reduced 
      Wnt5a expression in the PCLS hyperoxia model and in vivo mouse hyperoxia model, 
      with improved alveolarization in the PCLS model.Conclusions: Increased 
      mesenchymal Wnt5A during saccular-stage hyperoxia injury contributes to the 
      impaired alveolarization and septal thickening observed in BPD. Precise targeting 
      of Wnt5A may represent a potential therapeutic strategy for the treatment of BPD.
FAU - Sucre, Jennifer M S
AU  - Sucre JMS
AUID- ORCID: 0000-0002-6613-1439
AD  - Mildred Stahlman Division of Neonatology, Department of Pediatrics.
AD  - Department of Cell and Developmental Biology, and.
FAU - Vickers, Kasey C
AU  - Vickers KC
AD  - Division of Cardiovascular Medicine, Department of Medicine.
FAU - Benjamin, John T
AU  - Benjamin JT
AD  - Mildred Stahlman Division of Neonatology, Department of Pediatrics.
FAU - Plosa, Erin J
AU  - Plosa EJ
AD  - Mildred Stahlman Division of Neonatology, Department of Pediatrics.
FAU - Jetter, Christopher S
AU  - Jetter CS
AD  - Mildred Stahlman Division of Neonatology, Department of Pediatrics.
FAU - Cutrone, Alissa
AU  - Cutrone A
AD  - Medical Scientist Training Program, Vanderbilt University School of Medicine, 
      Nashville, Tennessee.
FAU - Ransom, Meaghan
AU  - Ransom M
AD  - Department of Pediatrics.
FAU - Anderson, Zachary
AU  - Anderson Z
AD  - Department of Pediatrics.
FAU - Sheng, Quanhu
AU  - Sheng Q
AD  - Department of Biostatistics.
FAU - Fensterheim, Benjamin A
AU  - Fensterheim BA
AD  - Medical Scientist Training Program, Vanderbilt University School of Medicine, 
      Nashville, Tennessee.
FAU - Ambalavanan, Namasivayam
AU  - Ambalavanan N
AD  - Division of Neonatology, Department of Pediatrics, University of Alabama at 
      Birmingham, Birmingham, Alabama.
FAU - Millis, Bryan
AU  - Millis B
AD  - Department of Cell and Developmental Biology, and.
AD  - Cell Imaging Shared Resource, Vanderbilt University, Nashville, Tennessee.
FAU - Lee, Ethan
AU  - Lee E
AD  - Department of Cell and Developmental Biology, and.
FAU - Zijlstra, Andries
AU  - Zijlstra A
AD  - Department of Pathology, Microbiology, and Immunology, and.
FAU - Konigshoff, Melanie
AU  - Konigshoff M
AUID- ORCID: 0000-0001-9414-5128
AD  - Division of Pulmonary Sciences and Critical Care Medicine, Department of 
      Medicine, University of Colorado, Denver, Colorado; and.
FAU - Blackwell, Timothy S
AU  - Blackwell TS
AD  - Department of Cell and Developmental Biology, and.
AD  - Division of Allergy, Pulmonary and Critical Care Medicine, Department of 
      Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
AD  - Nashville Veterans Affairs Medical Center, Nashville, Tennessee.
FAU - Guttentag, Susan H
AU  - Guttentag SH
AUID- ORCID: 0000-0003-4420-5879
AD  - Mildred Stahlman Division of Neonatology, Department of Pediatrics.
LA  - eng
GR  - K22 HL113039/HL/NHLBI NIH HHS/United States
GR  - P01 HL092870/HL/NHLBI NIH HHS/United States
GR  - R01 GM108807/GM/NIGMS NIH HHS/United States
GR  - P30 DK058404/DK/NIDDK NIH HHS/United States
GR  - R01 HL127173/HL/NHLBI NIH HHS/United States
GR  - K08 HL143051/HL/NHLBI NIH HHS/United States
GR  - R01 HL128996/HL/NHLBI NIH HHS/United States
GR  - U01 HL101794/HL/NHLBI NIH HHS/United States
GR  - L40 HL138848/HL/NHLBI NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - U01 HL122626/HL/NHLBI NIH HHS/United States
GR  - R01 HL129907/HL/NHLBI NIH HHS/United States
GR  - P01 HL116263/HL/NHLBI NIH HHS/United States
GR  - R01 CA218526/CA/NCI NIH HHS/United States
GR  - R01 HL141380/HL/NHLBI NIH HHS/United States
GR  - K12 HD087023/HD/NICHD NIH HHS/United States
GR  - K08 HL127102/HL/NHLBI NIH HHS/United States
GR  - R35 GM122516/GM/NIGMS NIH HHS/United States
GR  - R01 HL085317/HL/NHLBI NIH HHS/United States
GR  - P30 DK020593/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Am J Respir Crit Care Med
JT  - American journal of respiratory and critical care medicine
JID - 9421642
RN  - 0 (3-(4-methylphenylsulfonyl)-2-propenenitrile)
RN  - 0 (NF-kappa B)
RN  - 0 (Nitriles)
RN  - 0 (Sulfones)
RN  - 0 (Wnt-5a Protein)
SB  - IM
CIN - Am J Respir Crit Care Med. 2020 May 15;201(10):1174-1176. PMID: 32101467
MH  - Alveolar Epithelial Cells/*metabolism
MH  - Animals
MH  - Bronchopulmonary Dysplasia
MH  - Coculture Techniques
MH  - Fibroblasts/*metabolism
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Developmental
MH  - Humans
MH  - Hyperoxia/*genetics/metabolism
MH  - In Situ Hybridization
MH  - Lung/growth & development/*metabolism
MH  - Mesenchymal Stem Cells/drug effects/*metabolism
MH  - Mice
MH  - Microscopy, Confocal
MH  - NF-kappa B/antagonists & inhibitors
MH  - Nitriles/pharmacology
MH  - Organ Culture Techniques
MH  - Real-Time Polymerase Chain Reaction
MH  - Sulfones/pharmacology
MH  - Wnt-5a Protein/drug effects/*genetics/metabolism
PMC - PMC7233334
OTO - NOTNLM
OT  - Wnt
OT  - bronchopulmonary dysplasia
OT  - hyperoxia
OT  - lung injury
EDAT- 2020/02/06 06:00
MHDA- 2020/08/18 06:00
PMCR- 2021/05/15
CRDT- 2020/02/06 06:00
PHST- 2020/02/06 06:00 [pubmed]
PHST- 2020/08/18 06:00 [medline]
PHST- 2020/02/06 06:00 [entrez]
PHST- 2021/05/15 00:00 [pmc-release]
AID - 10.1164/rccm.201908-1513OC [doi]
PST - ppublish
SO  - Am J Respir Crit Care Med. 2020 May 15;201(10):1249-1262. doi: 
      10.1164/rccm.201908-1513OC.