ArticleAmerican journal of physiology. Lung cellular and molecular physiology2014
Nox2-dependent glutathionylation of endothelial NOS leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury.
Article in American journal of physiology. Lung cellular and molecular physiology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 47 citations in OpenAlex.
- Utility of low-dose oral aspirin challenges for diagnosis of aspirin-exacerbated respiratory disease.Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology · 2016Trial
- Oxidative Stress, Environmental Pollutants, Aging, and Epigenetic Regulation: Mechanistic Insights and Biomarker Advances.Antioxidants (Basel, Switzerland) · 2026Review
- Redox Regulation of Microvascular Physiology and Pathophysiology: Insights into Therapeutic Strategies and Limitations.Antioxidants & redox signaling · 2025Review
- Endothelial Reactive Oxygen Species: Key Players in Cardiovascular Health and Disease.Antioxidants & redox signaling · 2025Review
- Modification of extracellular matrix proteins by oxidants and electrophiles.Biochemical Society transactions · 2024Review
- Corilagin Inhibits Neutrophil Extracellular Trap Formation and Protects against Hydrochloric Acid/Lipopolysaccharide-Induced Acute Lung Injury in Mice by Suppressing the STAT3 and NOX2 Signaling Pathways.Antioxidants (Basel, Switzerland) · 2024Article
- Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS).Respiratory research · 2024Review
- Reactive Oxygen Species in the Aorta and Perivascular Adipose Tissue Precedes Endothelial Dysfunction in the Aorta of Mice with a High-Fat High-Sucrose Diet and Additional Factors.International journal of molecular sciences · 2023Article
- NOX2 and NOX5 are increased in cardiac microvascular endothelium of deceased COVID-19 patients.International journal of cardiology · 2023Article
- NADPH oxidase family proteins: signaling dynamics to disease management.Cellular & molecular immunology · 2022Review
- Mechanisms of decreased tubular flow-induced nitric oxide in Dahl salt-sensitive rat thick ascending limbs.American journal of physiology. Renal physiology · 2021Article
- Nutraceutical, Dietary, and Lifestyle Options for Prevention and Treatment of Ventricular Hypertrophy and Heart Failure.International journal of molecular sciences · 2021Review
- Oxidative stress and inflammation contribute to traffic noise-induced vascular and cerebral dysfunction via uncoupling of nitric oxide synthases.Redox biology · 2020Review
- Endothelial Dysfunction in Diabetes.Biomedicines · 2020Review
- Biomechanical Forces and Oxidative Stress: Implications for Pulmonary Vascular Disease.Antioxidants & redox signaling · 2019Review
- Cysteine Glutathionylation Acts as a Redox Switch in Endothelial Cells.Antioxidants (Basel, Switzerland) · 2019Review
- Toll-like receptor 3-mediated inflammation by p38 is enhanced by endothelial nitric oxide synthase knockdown.Cell communication and signaling : CCS · 2019Article
- New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease.International journal of molecular sciences · 2019Review
- Redox regulation of gasotransmission in the vascular system: A focus on angiogenesis.Free radical biology & medicine · 2017Review
- Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets.American journal of physiology. Lung cellular and molecular physiology · 2017Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
Microvascular barrier integrity is dependent on bioavailable nitric oxide (NO) produced locally by endothelial NO synthase (eNOS). Under conditions of limited substrate or cofactor availability or by enzymatic modification, eNOS may become uncoupled, producing superoxide in lieu of NO. This study was designed to investigate how eNOS-dependent superoxide production contributes to endothelial barrier dysfunction in inflammatory lung injury and its regulation. C57BL/6J mice were challenged with intratracheal LPS. Bronchoalveolar lavage fluid was analyzed for protein accumulation, and lung tissue homogenate was assayed for endothelial NOS content and function. Human lung microvascular endothelial cell (HLMVEC) monolayers were exposed to LPS in vitro, and barrier integrity and superoxide production were measured. Biopterin species were quantified, and coimmunoprecipitation (Co-IP) assays were performed to identify protein interactions with eNOS that putatively drive uncoupling. Mice exposed to LPS demonstrated eNOS-dependent increased alveolar permeability without evidence for altered canonical NO signaling. LPS-induced superoxide production and permeability in HLMVEC were inhibited by the NOS inhibitor nitro-l-arginine methyl ester, eNOS-targeted siRNA, the eNOS cofactor tetrahydrobiopterin, and superoxide dismutase. Co-IP indicated that LPS stimulated the association of eNOS with NADPH oxidase 2 (Nox2), which correlated with augmented eNOS S-glutathionylation both in vitro and in vivo. In vitro, Nox2-specific inhibition prevented LPS-induced eNOS modification and increases in both superoxide production and permeability. These data indicate that eNOS uncoupling contributes to superoxide production and barrier dysfunction in the lung microvasculature after exposure to LPS. Furthermore, the results implicate Nox2-mediated eNOS-S-glutathionylation as a mechanism underlying LPS-induced eNOS uncoupling in the lung microvasculature.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.