ArticleAmerican journal of respiratory and critical care medicine2017
Experimental Lung Injury Reduces Krüppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3-Rac1 Signaling.
Article in American journal of respiratory and critical care medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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37 citing papers in PubMed, 69 citations in OpenAlex.
- Active Endothelial Inactivation of Hyperpermeability: The Role of Nitric Oxide-Driven cAMP/Epac1 Signaling.Journal of cardiovascular development and disease · 2025Review
- Advancements in omics technologies: Molecular mechanisms of acute lung injury and acute respiratory distress syndrome (Review).International journal of molecular medicine · 2025Review
- Mechanism of KLF2 in young mice with pneumonia induced by Streptococcus pneumoniae.Journal of cardiothoracic surgery · 2024Article
- Krüppel-like factor 2 is an endoprotective transcription factor in diabetic kidney disease.American journal of physiology. Cell physiology · 2024Review
- Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells.The Journal of cell biology · 2024Article
- Low or oscillatory shear stress and endothelial permeability in atherosclerosis.Frontiers in physiology · 2024Review
- Cyclic stretch promotes vascular homing of endothelial progenitor cells via Acsl1 regulation of mitochondrial fatty acid oxidation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Inosine: A broad-spectrum anti-inflammatory against SARS-CoV-2 infection-induced acute lung injury via suppressing TBK1 phosphorylation.Journal of pharmaceutical analysis · 2023Article
- KLF2 alleviates endothelial cell injury and inhibits the formation of THP‑1 macrophage‑derived foam cells by activating Nrf2 and enhancing autophagy.Experimental and therapeutic medicine · 2022Article
- Targeting mechanosensitive endothelial TXNDC5 to stabilize eNOS and reduce atherosclerosis in vivo.Science advances · 2022Article
- Mechanotransduction Regulates the Interplays Between Alveolar Epithelial and Vascular Endothelial Cells in Lung.Frontiers in physiology · 2022Review
- Tetramethylpyrazine ameliorates acute lung injury by regulating the Rac1/LIMK1 signaling pathway.Frontiers in pharmacology · 2022Article
- Simvastatin Inhibits NLRP3 Inflammasome Activation and Ameliorates Lung Injury in Hyperoxia-Induced Bronchopulmonary Dysplasia via the KLF2-Mediated Mechanism.Oxidative medicine and cellular longevity · 2022Article
- Targeted polyelectrolyte complex micelles treat vascular complications in vivo.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- SARS-CoV-2 Infection Is Associated with Reduced Krüppel-like Factor 2 in Human Lung Autopsy.American journal of respiratory cell and molecular biology · 2021Article
- The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction.Signal transduction and targeted therapy · 2021Article
- MiR-144-induced KLF2 inhibition and NF-kappaB/CXCR1 activation promote neutrophil extracellular trap-induced transfusion-related acute lung injury.Journal of cellular and molecular medicine · 2021Article
- Single-cell metabolic imaging reveals a SLC2A3-dependent glycolytic burst in motile endothelial cells.Nature metabolism · 2021Article
- Mechanisms of Mechanical Force Induced Pulmonary Vascular Endothelial Hyperpermeability.Frontiers in physiology · 2021Review
- Mechanical forces and metabolic changes cooperate to drive cellular memory and endothelial phenotypes.Current topics in membranes · 2021Review
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
Abstract
rationaleAcute respiratory distress syndrome (ARDS) is caused by widespread endothelial barrier disruption and uncontrolled cytokine storm. Genome-wide association studies (GWAS) have linked multiple genes to ARDS. Although mechanosensitive transcription factor Krüppel-like factor 2 (KLF2) is a major regulator of endothelial function, its role in regulating pulmonary vascular integrity in lung injury and ARDS-associated GWAS genes remains poorly understood.
objectivesTo examine KLF2 expression in multiple animal models of acute lung injury and further elucidate the KLF2-mediated pathways involved in endothelial barrier disruption and cytokine storm in experimental lung injury.
methodsAnimal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis factor-α, LPS, mechanical stretch/ventilation, or microvascular flow. KLF2 manipulation, permeability measurements, small GTPase activity, luciferase assays, chromatin immunoprecipitation assays, and network analyses were used to determine the mechanistic roles of KLF2 in regulating endothelial monolayer integrity, ARDS-associated GWAS genes, and lung pathophysiology. MEASUREMENTS AND MAIN
resultsKLF2 is significantly reduced in several animal models of acute lung injury. Microvascular endothelial KLF2 is significantly induced by capillary flow but reduced by pathologic cyclic stretch and inflammatory stimuli. KLF2 is a novel activator of small GTPase Ras-related C3 botulinum toxin substrate 1 by transcriptionally controlling Rap guanine nucleotide exchange factor 3/exchange factor directly activated by cyclic adenosine monophosphate, which maintains vascular integrity. KLF2 regulates multiple ARDS GWAS genes related to cytokine storm, oxidation, and coagulation in lung microvascular endothelium. KLF2 overexpression ameliorates LPS-induced lung injury in mice.
conclusionsDisruption of endothelial KLF2 results in dysregulation of lung microvascular homeostasis and contributes to lung pathology in ARDS.
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