低氧性肺动脉高压（HPH）是慢性呼吸系统疾病常见并发症，病死率高，以肺血管重塑为主要病理特征，但形成机制尚不明确，其原因可能是低氧和其他炎症性刺激使肺血管内皮细胞功能紊乱及异常增殖所致。课题组研究发现肺动脉高压患者和HPH模型小鼠肺组织中炎症因子IL-33及受体ST2表达增加；敲除St2基因可明显减轻HPH模型鼠肺血管重塑，并下调HIF-1α、VEGF和VEGFR表达。故此我们认为低氧可能通过上调肺血管内皮细胞IL-33及受体ST2的表达，继而经HIF-1α、VEGF通路刺激内皮细胞等血管结构细胞和周围炎性细胞释放相关介质导致低氧性肺血管重塑。本研究拟通过敲除小鼠或内皮细胞的相关基因制备HPH模型，采用Real-time PCR、Western blot、基因沉默等方法从组织、细胞和分子水平，探讨IL-33/ST2应答轴在低氧性肺血管重塑形成过程中的作用机制，为HPH治疗提供新的理论依据。

Hypoxic pulmonary hypertension (HPH) is a common complication of chronic respiratory diseases, with high mortality. Pulmonary vascular remodeling is the major pathological feature, but the pathogenesis is still unclear. The possible reason may be due to hypoxia and other inflammatory stimulation which cause dysfunction and abnormal proliferation of pulmonary vascular endothelial cells. Our group found that the expressions of inflammatory cytokine IL-33 and its receptor ST2 were elevated in lung tissues of patients with pulmonary hypertension and of murine model of HPH. Knock-out of the St2 gene significantly reduced the pulmonary vascular remodeling. In addition, the expressions of hypoxia-inducible factor-1α(HIF-1α), vascular endothelial growth factor (VEGF) and its receptor VEGFR also decreased in lung tissue of St2 knock-out mice. These data indicated that hypoxia is able to induce the upregulation of IL-33 and its receptor in pulmonary artery endothelial cells. Therefore, we believe that hypoxia may upregulate expression of IL-33 and its receptor ST2;IL-33/ST2 axis, with HIF-1α and VEGF pathways together further stimulates endothelial cells, structural cells of vasculature and infiltrating inflammatory cells to release related mediators involved in hypoxic pulmonary vascular remodeling. In this project, we aim to establish HPH murine and vascular cellular models using relevant gene knock-out methods. Furthermore, Real-time PCR, Western blot, gene silencing and other techniques will be employed to investigate effects of IL-33/ST2 axis in the pathogenesis of hypoxic pulmonary vascular remodeling, at tissue, cellular and molecular levels. We hope that these studies will provide novel theoretical basis for HPH treatment.