ArticleThe Journal of biological chemistry2023
Spleen Tyrosine Kinase phosphorylates VE-cadherin to cause endothelial barrier disruption in acute lung injury.
Article in The Journal of biological chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 6 citations in OpenAlex.
- Macrophage polarization plasticity in pulmonary fibrosis: a review from pathogenesis to therapeutic targeting.Inflammopharmacology · 2026Review
- [Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2026Article
- The landscape of protein post-translational modifications in the pathogenesis of acute respiratory distress syndrome.Journal of thoracic disease · 2026Review
- Low-density neutrophil heterogeneity and spleen tyrosine kinase as therapeutic targets in sepsis.JCI insight · 2026Article
- Extracellular Vesicles as Drivers of Lung Endothelial Dysfunction in ARDS: Mechanisms and Therapeutic Opportunities.Comprehensive Physiology · 2026Review
- Elevated Spleen Tyrosine Kinase in Low-Density Neutrophils During Bacterial Sepsis in a Nonhuman Primate Model.The Journal of infectious diseases · 2025Article
- The Crucial Roles of Platelets as Immune Mediators in Sepsis.Journal of inflammation research · 2025Review
- Vascular syk-ness: A new role for an old immunological favorite.The Journal of biological chemistry · 2024Article
- Spleen tyrosine kinase: a novel pharmacological target for sepsis-induced cardiac dysfunction and multi-organ failure.Frontiers in immunology · 2024Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Increased endothelial cell (EC) permeability is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Tyrosine phosphorylation of VE-cadherin is a key determinant of EC barrier disruption. However, the identity and role of tyrosine kinases in this context are incompletely understood. Here we report that Spleen Tyrosine Kinase (Syk) is a key mediator of EC barrier disruption and lung vascular leak in sepsis. Inhibition of Syk by pharmacological or genetic approaches, each reduced thrombin-induced EC permeability. Mechanistically, Syk associates with and phosphorylates VE-cadherin to cause EC permeability. To study the causal role of endothelial Syk in sepsis-induced ALI, we used a remarkably efficient and cost-effective approach based on gene transfer to generate EC-ablated Syk mice. These mice were protected against sepsis-induced loss of VE-cadherin and inflammatory lung injury. Notably, the administration of Syk inhibitor R788 (fostamatinib); currently in phase II clinical trial for the treatment of COVID-19, mitigated lung injury and mortality in mice with sepsis. These data identify Syk as a novel kinase for VE-cadherin and a druggable target against ALI in sepsis.
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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.