PMID- 35662702
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220716
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through 
      Mitochondrial Reactive Oxygen Species.
PG  - 880878
LID - 10.3389/fphar.2022.880878 [doi]
LID - 880878
AB  - Management of acute respiratory distress involves O(2) supplementation, which is 
      lifesaving, but causes severe hyperoxic acute lung injury (HALI). NADPH oxidase 
      (NOX) could be a major source of reactive oxygen species (ROS) in hyperoxia (HO). 
      Epithelial cell death is a crucial step in the development of many lung diseases. 
      Alveolar type II (AT2) cells are the metabolically active epithelial cells of 
      alveoli that serve as a source of AT1 cells following lung injury. The aim of 
      this study was to determine the possible role of AT2 epithelial cell NOX4 in 
      epithelial cell death from HALI. Wild type (WT), Nox4 (fl/fl) (control), and Nox4 
      (-/-) Spc-Cre mice were exposed to room air (NO) or 95% O(2) (HO) to investigate 
      the structural and functional changes in the lung. C57BL/6J WT animals subjected 
      to HO showed increased expression of lung NOX4 compared to NO. Significant HALI, 
      increased bronchoalveolar lavage cell counts, increased protein levels, elevated 
      proinflammatory cytokines and increased AT2 cell death seen in hyperoxic Nox4 
      (fl/fl) control mice were attenuated in HO-exposed Nox4 (-/-) Spc-Cre mice. 
      HO-induced expression of NOX4 in MLE cells resulted in increased mitochondrial 
      (mt) superoxide production and cell apoptosis, which was reduced in NOX4 siRNA 
      silenced cells. This study demonstrates a novel role for epithelial cell NOX4 in 
      accelerating lung epithelial cell apoptosis from HALI. Deletion of the Nox4 gene 
      in AT2 cells or silencing NOX4 in lung epithelial cells protected the lungs from 
      severe HALI with reduced apoptosis and decreased mt ROS production in HO. These 
      results suggest NOX4 as a potential target for the treatment of HALI.
CI  - Copyright (c) 2022 Harijith, Basa, Ha, Thomas, Jafri, Fu, MacFarlane, Raffay, 
      Natarajan and Sudhadevi.
FAU - Harijith, Anantha
AU  - Harijith A
AD  - Department of Pediatrics, School of Medicine, Case Western Reserve University, 
      Cleveland, OH, United States.
FAU - Basa, Prathima
AU  - Basa P
AD  - Department of Pediatrics, School of Medicine, Case Western Reserve University, 
      Cleveland, OH, United States.
FAU - Ha, Alison
AU  - Ha A
AD  - Department of Pediatrics, School of Medicine, Case Western Reserve University, 
      Cleveland, OH, United States.
AD  - Department of Biochemistry and Molecular Genetics, College of Medicine, 
      University of Illinois at Chicago, Chicago, IL, United States.
FAU - Thomas, Jaya
AU  - Thomas J
AD  - Department of Pediatrics, School of Medicine, Case Western Reserve University, 
      Cleveland, OH, United States.
FAU - Jafri, Anjum
AU  - Jafri A
AD  - Department of Genetics and Genome Sciences, School of Medicine, Case Western 
      Reserve University, Cleveland, OH, United States.
FAU - Fu, Panfeng
AU  - Fu P
AD  - Department of Pharmacology and Regenerative Medicine, University of Illinois at 
      Chicago, Chicago, IL, United States.
FAU - MacFarlane, Peter M
AU  - MacFarlane PM
AD  - Department of Pediatrics, School of Medicine, Case Western Reserve University, 
      Cleveland, OH, United States.
FAU - Raffay, Thomas M
AU  - Raffay TM
AD  - Department of Pediatrics, School of Medicine, Case Western Reserve University, 
      Cleveland, OH, United States.
FAU - Natarajan, Viswanathan
AU  - Natarajan V
AD  - Department of Pharmacology and Regenerative Medicine, University of Illinois at 
      Chicago, Chicago, IL, United States.
AD  - Department of Internal Medicine, College of Medicine, University of Illinois at 
      Chicago, Chicago, IL, United States.
FAU - Sudhadevi, Tara
AU  - Sudhadevi T
AD  - Department of Pediatrics, School of Medicine, Case Western Reserve University, 
      Cleveland, OH, United States.
LA  - eng
PT  - Journal Article
DEP - 20220519
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9160661
OTO - NOTNLM
OT  - NADPH oxidase 4
OT  - alveolar type 2 epithelial cell
OT  - apoptosis
OT  - hyperoxic acute lung injury
OT  - mitochondrial ROS
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/06/07 06:00
MHDA- 2022/06/07 06:01
PMCR- 2022/05/19
CRDT- 2022/06/06 13:46
PHST- 2022/02/22 00:00 [received]
PHST- 2022/04/18 00:00 [accepted]
PHST- 2022/06/06 13:46 [entrez]
PHST- 2022/06/07 06:00 [pubmed]
PHST- 2022/06/07 06:01 [medline]
PHST- 2022/05/19 00:00 [pmc-release]
AID - 880878 [pii]
AID - 10.3389/fphar.2022.880878 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 May 19;13:880878. doi: 10.3389/fphar.2022.880878. 
      eCollection 2022.