RECIPROCAL REGULATION OF SDF-1 BETWEEN MARROW AND LUNG DURING ACUTE LUNG INJURY

急性肺损伤期间骨髓和肺​​之间 SDF-1 的相互调节

• 批准号: 7609703
• 负责人: BENJAMIN T SURATT
• 金额: $ 25.2万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7609703
• 关键词: Acute Lung Injury; Address; Animal Model; Bone Marrow; CXC Chemokines; Cells; Computer Retrieval of Information on Scientific Projects Database; Condition; Development; Down-Regulation; Elastases; Event; Funding; Grant; Granulocyte Colony-Stimulating Factor; Institution; Lead; Leukocyte Elastase; Lung; Lung Inflammation; Marrow; Mediating; Neutrophil Infiltration; Neutrophilia; Pancreatic Elastase; Pathogenesis; Patients; Phase; Recruitment Activity; Regulation; Research; Research Personnel; Resources; Role; Severities; Signal Transduction; Source; Testing; United States National Institutes of Health; clinical Diagnosis; improved; injured; mortality; neutrophil

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The recruitment of neutrophils to the lung is a pivotal factor in the development and perpetuation of acute lung injury (ALI). A rapid, early influx of mature circulating neutrophils to the injured lung is followed by a slower, sustained recruitment of more immature neutrophils from the bone marrow. Much of the progressive damage to the lung that characterizes ALI is attributable to this second, persistent phase of neutrophilia, and its duration and severity are predictors of mortality. Although many of the signals governing the initial influx of neutrophils to the lung in ALI have been delineated, the mechanisms governing the marrow release and lung recruitment of this subsequent, persistent wave of neutrophils are poorly understood. Previously, we have shown that expression of the CXC chemokine Stromal Derived Factor-1 (SDF-1) in bone marrow is critical for the retention of marrow neutrophils under homeostatic conditions. We now have evidence that marrow SDF-1 is decreased during ALI, and that its downregulation occurs through a neutrophil elastase-dependent mechanism initiated by Granulocyte-Colony Stimulating Factor (G-CSF). Further, pulmonary expression of SDF-1 is increased during ALI, and is critical for the late influx of neutrophils to the lung during the progression of ALI. We hypothesize that the persistent influx of neutrophils to the lung in ALI is driven by: 1) G-CSF- initiated, elastase-mediated, degradation of marrow SDF-1, leading to release of marrow neutrophils, and, 2) Simultaneous increase of pulmonary SDF-1, which serves to recruit these newly-released cells. Using animal models of ALI, we are testing these hypotheses in the following Specific Aims: 1) To determine whether neutrophil elastase-mediated degradation of marrow SDF-1 is responsible for the release of marrow neutrophils in the persistent phase of ALI; 2) To investigate whether G-CSF initiates the loss of marrow SDF-1 during ALI; 3) To address the role of lung SDF-1 in the recruitment of circulating marrow neutrophils during the persistent phase of ALI. The diagnosis of clinical ALI is typically delayed until after the best-studied events in its pathogenesis have occurred, and the patient has entered the persistent phase of lung inflammation. The studies we propose are expected to improve our limited understanding of this phase of ALI, and could eventually lead to improved therapies for a condition that continues to be all too often fatal.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 中性粒细胞向肺部的募集是急性肺损伤（ALI）发生和持续的关键因素。成熟的循环中性粒细胞快速、早期地流入受伤的肺部，随后从骨髓中缓慢、持续地招募更多未成熟的中性粒细胞。以 ALI 为特征的肺部进行性损伤大部分可归因于中性粒细胞增多的第二个持续阶段，其持续时间和严重程度是死亡率的预测因素。尽管在 ALI 中控制中性粒细胞最初流入肺部的许多信号已经被描述出来，但控制骨髓释放和肺招募随后持续的中性粒细胞波的机制仍知之甚少。 此前，我们已经证明，骨髓中 CXC 趋化因子基质衍生因子 1 (SDF-1) 的表达对于在稳态条件下保留骨髓中性粒细胞至关重要。我们现在有证据表明，ALI 期间骨髓 SDF-1 减少，并且其下调是通过粒细胞集落刺激因子 (G-CSF) 启动的中性粒细胞弹性蛋白酶依赖性机制发生的。 此外，SDF-1 的肺部表达在 ALI 期间增加，对于 ALI 进展期间中性粒细胞后期流入肺部至关重要。 我们假设 ALI 中中性粒细胞持续流入肺部是由以下因素驱动的：1) G-CSF 启动、弹性蛋白酶介导的骨髓 SDF-1 降解，导致骨髓中性粒细胞释放，2) 同时增加肺 SDF-1，其作用是招募这些新释放的细胞。 使用 ALI 动物模型，我们正在以下具体目标中测试这些假设： 1) 确定中性粒细胞弹性蛋白酶介导的骨髓 SDF-1 降解是否是 ALI 持续期骨髓中性粒细胞释放的原因； 2) 研究G-CSF是否引发ALI期间骨髓SDF-1的损失； 3) 探讨肺 SDF-1 在 ALI 持续期募集循环骨髓中性粒细胞中的作用。 临床 ALI 的诊断通常会延迟到对其发病机制进行了充分研究的事件发生之后，并且患者已进入肺部炎症的持续阶段。我们提出的研究预计将提高我们对这一阶段 ALI 的有限了解，并最终可能改进对这种常常致命的疾病的治疗方法。