摘要：SummaryRadiation-induced lung injury is a common late side effect of thoracic radiotherapy. Endothelial dysfunction following leukocytes infiltration is a prominent feature in this process. Here, we established a clinical-mimicking mouse model of radiation-induced lung injury and found the activity of phosphatase Shp2 was elevated in endothelium after injury. Endothelium-specific Shp2 deletion mice showed relieved collagen deposition along with disrupted radiation-induced Jag1 expression in the endothelium. Furthermore, endothelium-derived Jag1 activated the alternative activation of macrophagesin vitroandin vivoby paracrine Notch signaling. Consistently, the Notch pathway was significantly activated by chest irradiation in the peripheral blood leukocytes of patients with cancer. Collectively, our work demonstrates that Shp2 participates in the radiation-induced endothelial dysfunction and subsequently inflammatory microenvironment producing during radiation-induced lung injury. Our findings indicate Shp2 as a potential target for radiation-induced lung injury and provide another way for endothelium to participate in the pathological process of radiation-induced lung injury.Graphical abstractDisplay OmittedHighlights•Phosphatase activity of endothelial Shp2 is elevated by irradiationin vitroandin vivo•Radiation-induced Jag1 is blocked in Shp2-deficient endothelium•Loss of Shp2 in endothelium relieves radiation-induced pulmonary injury•Shp2-deficient endothelium restrains macrophage activation via Notch signalingBiological sciences; Immunology; Molecular biology; Transcriptomics
