Inhibition of EphA2 by Dasatinib Suppresses Radiation-Induced Intestinal Injury.

Areumnuri Kim,Seung Sook Lee,You Yeon Choi,Sunhoo Park,Ki Moon Seong,Sehwan Shim

doi:10.3390/ijms21239096

Abstract

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.

Highlights

Exposure to high-dose radiation can result in malfunction of the bone marrow, heart, brain, gastrointestinal tract, and lung because these tissues have high concentrations of radiosensitive vascular layers such as endothelial and epithelial cells [1]
Based on the above results, we explored that radiation-activated Eph–ephrin signaling promotes the inflammatory response both in vitro and in vivo
To determine whether increased vascular permeability leads to recruitment of immune cells into inflamed tissues, the intestinal lamina propria of irradiated mice were investigated at 3 days after radiation exposure

Summary

Introduction

Exposure to high-dose radiation can result in malfunction of the bone marrow, heart, brain, gastrointestinal tract, and lung because these tissues have high concentrations of radiosensitive vascular layers such as endothelial and epithelial cells [1]. Previous clinical and experimental studies have shown that radiation-induced vascular damage contributes to systemic tissue injury, thereby accelerating accumulation of lipids, inflammation, and thrombosis [3,4,5]. To prevent and manage the vascular injury by radiation, early assessment technologies that can physically measure structural changes in blood vessels and blood flow are needed. Various vascular assessments approached predicting the region of vascular disease using nanofluidic devices. These physically analyzed methods can be assessing non-invasive measurement techniques for the promotion of early clinical detection of vascular disease [7,8]. Due to the lack of data on the underlying molecular and pathological mechanisms of radiation-induced tissue damage, there are no established therapeutic drugs available to treat such injury

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Discussion

Conclusion