International journal of molecular sciences, 2020-11, Vol.21 (23), p.9096
2020
Details
- Autor(en) / Beteiligte
- Titel
- Inhibition of EphA2 by Dasatinib Suppresses Radiation-Induced Intestinal Injury
- Ist Teil von
- International journal of molecular sciences, 2020-11, Vol.21 (23), p.9096
- Ort / Verlag
- Switzerland: MDPI AG
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- Radiation-induced multiorgan dysfunction is thought to result primarily from damage to the endothelial system, leading to a systemic inflammatory response that is mediated by the recruitment of leukocytes. The Eph-ephrin signaling pathway in the vascular system participates in various disease developmental processes, including cancer and inflammation. In this study, we demonstrate that radiation exposure increased intestinal inflammation via endothelial dysfunction, caused by the radiation-induced activation of EphA2, an Eph receptor tyrosine kinase, and its ligand ephrinA1. Barrier dysfunction in endothelial and epithelial cells was aggravated by vascular endothelial-cadherin disruption and leukocyte adhesion in radiation-induced inflammation both in vitro and in vivo. Among all Eph receptors and their ligands, EphA2 and ephrinA1 were required for barrier destabilization and leukocyte adhesion. Knockdown of EphA2 in endothelial cells reduced radiation-induced endothelial dysfunction. Furthermore, pharmacological inhibition of EphA2-ephrinA1 by the tyrosine kinase inhibitor dasatinib attenuated the loss of vascular integrity and leukocyte adhesion in vitro. Mice administered dasatinib exhibited resistance to radiation injury characterized by reduced barrier leakage and decreased leukocyte infiltration into the intestine. Taken together, these data suggest that dasatinib therapy represents a potential approach for the protection of radiation-mediated intestinal damage by targeting the EphA2-ephrinA1 complex.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1422-0067, 1661-6596eISSN: 1422-0067DOI: 10.3390/ijms21239096Titel-ID: cdi_doaj_primary_oai_doaj_org_article_9c39a3a016ec41df8b9d91cb2fbb5843
- Format
- –
- Schlagworte
- Adhesion, Animals, Cadherin, Cell adhesion & migration, Cell Adhesion - drug effects, Cell Adhesion - radiation effects, Cell Membrane Permeability - drug effects, Cell Membrane Permeability - radiation effects, dasatinib, Dasatinib - pharmacology, Dasatinib - therapeutic use, Destabilization, Disease, Down-Regulation - drug effects, Down-Regulation - radiation effects, Endothelial cells, Endothelium, Endothelium, Vascular - drug effects, Endothelium, Vascular - pathology, Endothelium, Vascular - radiation effects, Enzyme inhibitors, Eph protein, EphA2, EphA2 protein, Ephrin-A1 - metabolism, Epithelial cells, Human Umbilical Vein Endothelial Cells - drug effects, Human Umbilical Vein Endothelial Cells - radiation effects, Humans, Inflammation, Inflammatory response, Injury prevention, intestinal injury, Intestine, Intestines - drug effects, Intestines - injuries, Intestines - pathology, Intestines - radiation effects, Kinases, Leukocytes, Leukocytes - drug effects, Leukocytes - radiation effects, Ligands, Male, Measurement techniques, Mice, Inbred C57BL, Neutrophils, Permeability, Phosphorylation, Phosphorylation - drug effects, Phosphorylation - radiation effects, Protein-tyrosine kinase receptors, Proteins, radiation, Radiation damage, Radiation effects, Radiation injuries, Radiation Injuries - drug therapy, Radiation tolerance, Radiation, Ionizing, Receptor, EphA2 - antagonists & inhibitors, Receptor, EphA2 - metabolism, Receptors, Signal transduction, Tyrosine, Vascular system