NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species
Management of acute respiratory distress involves O2 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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.880878/full |
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| author | Anantha Harijith Prathima Basa Alison Ha Alison Ha Jaya Thomas Anjum Jafri Panfeng Fu Peter M. MacFarlane Thomas M. Raffay Viswanathan Natarajan Viswanathan Natarajan Tara Sudhadevi |
| author_facet | Anantha Harijith Prathima Basa Alison Ha Alison Ha Jaya Thomas Anjum Jafri Panfeng Fu Peter M. MacFarlane Thomas M. Raffay Viswanathan Natarajan Viswanathan Natarajan Tara Sudhadevi |
| author_sort | Anantha Harijith |
| collection | DOAJ |
| description | Management of acute respiratory distress involves O2 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), Nox4fl/fl (control), and Nox4−/−Spc-Cre mice were exposed to room air (NO) or 95% O2 (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 Nox4fl/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. |
| first_indexed | 2024-12-12T14:26:00Z |
| format | Article |
| id | doaj.art-f3ccbd489032403689598d814f9f2df6 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-12T14:26:00Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-f3ccbd489032403689598d814f9f2df62022-12-22T00:21:41ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-05-011310.3389/fphar.2022.880878880878NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen SpeciesAnantha Harijith0Prathima Basa1Alison Ha2Alison Ha3Jaya Thomas4Anjum Jafri5Panfeng Fu6Peter M. MacFarlane7Thomas M. Raffay8Viswanathan Natarajan9Viswanathan Natarajan10Tara Sudhadevi11Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesDepartment of Pharmacology and Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Internal Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, United StatesDepartment of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH, United StatesManagement of acute respiratory distress involves O2 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), Nox4fl/fl (control), and Nox4−/−Spc-Cre mice were exposed to room air (NO) or 95% O2 (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 Nox4fl/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.https://www.frontiersin.org/articles/10.3389/fphar.2022.880878/fullNADPH oxidase 4mitochondrial ROSalveolar type 2 epithelial cellapoptosishyperoxic acute lung injury |
| spellingShingle | Anantha Harijith Prathima Basa Alison Ha Alison Ha Jaya Thomas Anjum Jafri Panfeng Fu Peter M. MacFarlane Thomas M. Raffay Viswanathan Natarajan Viswanathan Natarajan Tara Sudhadevi NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species Frontiers in Pharmacology NADPH oxidase 4 mitochondrial ROS alveolar type 2 epithelial cell apoptosis hyperoxic acute lung injury |
| title | NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species |
| title_full | NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species |
| title_fullStr | NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species |
| title_full_unstemmed | NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species |
| title_short | NOX4 Mediates Epithelial Cell Death in Hyperoxic Acute Lung Injury Through Mitochondrial Reactive Oxygen Species |
| title_sort | nox4 mediates epithelial cell death in hyperoxic acute lung injury through mitochondrial reactive oxygen species |
| topic | NADPH oxidase 4 mitochondrial ROS alveolar type 2 epithelial cell apoptosis hyperoxic acute lung injury |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.880878/full |
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