Kidney Response to Sepsis Affects Angiogenic Balance and Likelihood of CCI & PICS

项目摘要 这个项目的总体假设是持续性炎症、免疫抑制和分解代谢 (图)是导致长期存活率下降的病理生理过程的标志， 慢性危重病(CCI)患者的功能能力同时髓系来源的持续性扩张 抑制细胞(MDSC；项目2)是免疫抑制和炎症的关键潜在机制 在CCI中，该项目研究了脓毒症时肾损害启动抗血管生成作用的机制。 在CCI中增强和维持炎症、免疫抑制和分解代谢的状态。在败血症期间， 感染通过Toll样受体和低氧导致低氧诱导因子(HIF)-1和 随后血管生成因子(促红细胞生成素和血管内皮生长因子)的上调 (血管内皮生长因子))。我们之前已经证明了异二聚体EPO受体(由EPO受体和 β共同受体(VEGFcr)与β受体2(VEGFR-2)相互作用动员骨髓来源 血管生成细胞，这可以促进内皮修复。促红细胞生成素和血管内皮细胞生长因子均可启动抗肿瘤免疫 可溶性VEGR-2(sFlt-1)和血管生成素-2(Ang-2)上调的血管生成反应。而sFlt-1 结合血管内皮生长因子降低其循环水平并抵消其作用，未对抗的EPO导致持久 SFlt-1、Ang-2升高和血管内皮生长因子抑制。我们的假设是，肾损伤的患者 在脓毒症中，相对于血管内皮生长因子，sFlt-1的刺激导致EPO反应过度 持续的抗血管生成(低水平的血管内皮生长因子和升高的血管紧张素-2)、炎性(升高的促红细胞生成素) 州政府。研究人员建议检查脓毒症患者的肾脏损害，作为抗血管生成的预测指标。 并确定抗血管生成平衡是否与血管扩张增加有关 MDSC(在项目2中确定)和PICS的可能性增加，其特征是病态的长期 结果(项目1)。EPO产量增加对MDSC扩张的直接影响将在 使用βcr基因敲除小鼠建立慢性脓毒症模型。

PROJECT ABSTRACT The overall hypothesis of this program is that persistent inflammation, immunosuppression and catabolism (PICS) are the hallmarks of pathophysiologic processes leading to decreases in long-term survival and functional capacity in patients with chronic critical illness (CCI). While persistent expansion of myeloid-derived suppressor cells (MDSC; Project #2) is a key underlying mechanism of immunosuppression and inflammation in CCI, this project investigates the mechanism by which kidney damage in sepsis initiates an anti-angiogenic state that augments and perpetuates inflammation, immunosuppression, and catabolism in CCI. During sepsis, infection, via toll-like receptors, and hypoxia leads to activation of hypoxia inducible factor (HIF)-1 and subsequent upregulation of angiogenic factors (erythropoietin (EPO) and vascular endothelial growth factor (VEGF)). We have previously shown that the heterodimeric EPO receptor (consisting of the EPO receptor and β-common receptor (βcR)) interacts with VEGF receptor 2 (VEGFR-2) to mobilize bone marrow derived angiogenic cells, which can contribute to the endothelial repair. EPO and VEGF can both initiate the anti- angiogenic response of upregulation of soluble VEGR-2 (sFlt-1) and angiopoietin-2 (ANG-2). While sFlt-1 binds VEGF reducing its circulating levels and counteracting its effect, unopposed EPO leads to persistent sFlt-1 and ANG-2 elevation and VEGF suppression. Our hypothesis, is that patients in whom kidney damage in sepsis results in an exaggerated EPO response, relative to VEGF, the stimulation of sFlt-1 leads to a persistence of an anti-angiogenic (low levels of VEGF and elevated ANG-2), inflammatory (elevated EPO) state. The investigators propose to examine kidney damage in septic patients as a predictor of anti-angiogenic imbalance and to determine whether anti-angiogenic balance is associated with increased expansion of MDSCs (as determined in Project #2) and increased likelihood of PICS, characterized by morbid long-term outcome (Project #1). The direct effect of increased EPO production on MDSC expansion will be tested in murine models of chronic sepsis using the βcR knockout mouse.