The Mechanism Of Endothelial Shp2 In Regulating Radiation-induced Pulmonary Fibrosis

Radiation-induced pulmonary fibrosis is a common clinical complication of radiotherapy for patients with thoracic tumors,characterized by progressive dyspnea and respiratory failure in clinical.With the advancement of tumor treatment,RIPF significantly reduced the quality and survival rate of patients,thus becoming an increasingly limiting factor in tumor treatment.However,there is still a lack of effective prediction methods and drug for treatment in clinical.Vascular endothelial cells are important components of the lung functional units,which are very sensitive to radiation.Endothelial dysfunction is a major feature of radiation-induced lung injury,and its role in the repair of tissue and organ damage caused by radiotherapy has received increasing attention recently.Endothelial cells are widely involved in the inflammation response and intracellular signal transduction after tissue injury,however,the role of endothelium in RIPF needs to be further explored.Reversible phosphorylation of proteins is the molecular basis for regulating of cell biological functions.Shp2,a tyrosine phosphatase encoded by the PTPN11,is involved in the regulation of a variety of physiological and pathological processes.Previous studies shows that Shp2 is a key regulator of endothelial function.Moreover,Shp2 is reported as a novel drug target for the treatment of tumors,regulating the occurrence and development of a variety of cancers.Our previous studies shows that Shp2 is also involved in the regulation of lung inflammation and bleomycin-induced fibrosis in mice.However,the molecular mechanism of Shp2 in RIPF have not been reported yet.RIPF is a complication of radiotherapy for vascular-rich tumors.Shp2 is not only a key regulator of vascular function and fibrosis,but also a new drug target for the treatment of tumors,its application as an anti-RIPF targetis promising.In this study,we found that the phosphatase activity and phosphorylation of Shp2 is upregulated by irradiation in vascular endothelial cells,proving that endothelial Shp2 is involved in the process of RIPF.Further investigate of mechanism shown that irradiation promotes the nuclear localization of β-catenin by elevating the phosphatase activity of Shp2,thereby activating the transcription and expression of Notch signaling pathway ligand Jag1.In vivo studies shown that collagen deposition and Jag1 expression in the lungs of Shp2 i ECKO mice are significantly reduced in both high-dose short-term and low-dose long-term RIPF models.Further analysis revealed that the irradiated vascular endothelial cells interact with neighboring macrophages in a paracrine manner through the Notch signaling pathway,thereby promoting the conversion of macrophages to a M2 type.Our study proved for the first time that endothelial Shp2 is a key regulator of RIPF and provides a new idea for endothelium involvement in the pathological process of pulmonary fibrosis,which builds a theoretical basis and experimental basis for clinical prevention and treatment of RIPF.