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

肾脏对脓毒症的反应影响血管生成平衡和 CCI 的可能性

• 批准号: 8740721
• 负责人: MARK S. SEGAL
• 金额: $ 29.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8740721
• 关键词: Activities of Daily Living; Acute; Affect; Angiogenic Factor; Angiopoietin-2; Angiopoietins; Animal Model; Animals; Automobile Driving; Binding; Biostatistics Core; Blood capillaries; Bone Marrow; Caring; Catabolism; Cell Count; Cells; Chemosensitization; Chronic; Chronic Kidney Failure; Clinical; Critical Care; Critical Illness; Data; Development; Equilibrium; Erythropoietin; Erythropoietin Receptor; Functional disorder; Grant; Hypoxia; Immunosuppression; Infection; Inflammation; Inflammatory; Intensive Care Units; Kidney; Knockout Mice; Lead; Ligation; Mediating; Modeling; Mus; Muscle; Myelogenous; Myeloid Cells; Natural Immunity; Nosocomial Infections; Nutritional status; Operative Surgical Procedures; Organ; Organ failure; Outcome; Patients; Play; Process; Production; Protein-Energy Malnutrition; Proteins; Puncture procedure; Recurrence; Relative (related person); Research Personnel; Resources; Role; Sepsis; Suppressor-Effector T-Lymphocytes; Testing; Toll-like receptors; Up-Regulation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Work; Wound Healing; capillary; data management; follow-up; human subject; hypoxia inducible factor 1; immunosuppressed; meetings; mortality; prevent; programs; receptor; repaired; response; septic; skills; wasting

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.

项目摘要 该计划的总体假设是持续的炎症、免疫抑制和分解代谢 (PICS) 是导致长期生存率和寿命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持续扩张髓源性。 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，该项目研究脓毒症肾损伤启动抗血管生成的机制 在脓毒症期间增强和维持炎症、免疫抑制和分解代谢。 通过 Toll 样受体进行感染，缺氧会导致缺氧诱导因子 (HIF)-1 的激活， 随后血管生成因子（促红细胞生成素（EPO）和血管内皮生长因子）上调 (VEGF))))。 β-共同受体 (βcR)) 与 VEGF 受体 2 (VEGFR-2) 相互作用以动员骨髓来源 有助于内皮修复的血管生成细胞和 VEGF 都可以启动抗-血管生成。 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。 结合 VEGF 降低其循环水平并抵消其作用，不受对抗的 EPO 会导致持续的 我们的假设是，sFlt-1 和 ANG-2 升高且 VEGF 受到抑制。 在脓毒症中，相对于 VEGF，sFlt-1 的刺激会导致 EPO 反应过度，从而导致 抗血管生成药物（低水平的 VEGF 和升高的 ANG-2）、炎症（升高的 EPO）持续存在 研究人员建议检查脓毒症患者的肾脏损伤作为抗血管生成的预测因子。 不平衡并确定抗血管生成平衡是否与血管扩张增加有关 MDSC（如项目 #2 中确定的）和 PICS 的可能性增加，其特征是长期病态 结果（项目#1）将在 MDSC 扩张中测试 EPO 产量增加的直接影响。 使用 βcR 敲除小鼠建立慢性脓毒症小鼠模型。