IL-33/ST2应答轴在低氧相关性肺动脉高压发病机制中的作用研究

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.

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。

低氧性肺动脉高压（Hypoxia-induced pulmonary hypertension, 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。本研究首先通过临床样本、在体动物模型和体外细胞模型实验探讨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。研究发现低氧可诱导肺血管内皮细胞上调表达IL-33及其受体ST2，通过增加其下游信号分子低氧诱导因子-1α（Hypoxia inducible factor-1α, HIF-1α）和血管内皮生长因子（Vascular endothelial growth factor, VEGF）的表达，导致低氧性肺血管重塑的发生，进而形成HPH。阻断该通路可逆转低氧性肺血管重塑形成，有效改善肺动脉高压；同时，低氧可通过促进IL-33/ST2表达增强进而诱导巨噬细胞内核转录因子（Nuclear factor kappa-B， NF-κB）通路的激活，导致促炎细胞因子白细胞介素-1（Interleukin 1，IL-1）和单核细胞趋化因子（Monocyte chemotactic protein 1, MCP-1）的产生，加重炎症反应并间接引起肺动脉血管重塑参与HPH的发生发展。其次，巨噬细胞通过糖酵解可促进其产生IL-33，而抑制糖酵解途径可能通过减少巨噬细胞来源的IL-33进而缓解肺动脉高压的发生发展。第三，长期暴露大气颗粒物（Particulate Matter, PM）可以导致肺血管重塑，肺动脉高压形成，而IL-33的受体St2基因敲除可改善PM导致的肺动脉高压表型。第四，研究还发现烯醇酶特异性抑制剂可减轻低氧性肺动脉高压的形成，并改善低氧性肺血管重塑和低氧所诱导的右心室肥厚。因此，低氧性肺动脉高压的发生机制错综复杂，除IL-33/ST2应答轴外，某些酶类介导的代谢重编程亦可能参与免疫细胞的调控进而导致疾病的发生发展。此外，课题组在上述研究基础上，明确发现IL-33/ST2应答轴在气道慢性疾病的炎症及组织重构过程中扮演着极为重要的角色，为深入探讨呼吸系统慢病的发生机制和筛选有效靶点奠定了必要的理论和实验基础。