Neutrophil Homeostasis and Lung Sequestration

描述(申请人提供)：炎症反应中性粒细胞的产生、释放和处置仍然知之甚少。包括成人呼吸窘迫综合征(ARDS)在内的许多中性粒细胞依赖型肺部疾病的特征是未成熟的中性粒细胞从骨髓释放到循环中。利用小鼠体内系统，一种新的胚胎干细胞来源的体外系统，以及体外的小鼠和人类细胞，我们建议检验相互关联的假设，以探索白细胞增多和肺隔离的基本机制。1.炎症过程中，肿瘤坏死因子和其他细胞因子诱导全身G-CSF的表达。G-CSF不仅增加了祖细胞的数量，而且还延缓了发育中的中性粒细胞的凋亡，放大了由此产生的中性粒细胞。2.G-CSF通过SDF-1对CXCR4的信号转导、唾液粘附素与其配体的相互作用、基质与造血细胞表面的alcam同型相互作用三个系统的修饰来动员未成熟的中性粒细胞。3.G-CSF动员的未成熟中性粒细胞体积较大，对变形的抵抗力增强，导致其定位于肺内。我们相信，这些实验的结果将提供关于正常内稳态的基本方面的新信息，以及对中性粒细胞依赖的炎症状态的机制的洞察。

DESCRIPTION (provided by applicant): The generation, release, and disposal of neutrophils in response to inflammation remains poorly understood. A number of neutrophil-dependent lung disorders, including the Adult Respiratory Distress Syndrome (ARDS) are characterized by release of immature neutrophils from marrow into the circulation. Using murine systems in vivo, a novel embryonic stem cell-derived in vitro system, and murine and human cells in vitro, we propose to test interrelated hypotheses that explore fundamental mechanisms of leukocytosis and lung sequestration. 1. During inflammation, systemic expression of G-CSF is induced by TNF and other cytoses. G-CSF not only increases the number of progenitors, but also retards apoptosis of developing neutrophils, amplifying the resultant generation of neutrophils. 2. G-CSF mobilizes immature neutrophils through modification of three systems - signaling of CXCR4 by SDF-1, the interaction between sialoadhesin and its ligand, and homotypic interactions between ALCAM on both stroma and hematopoietic cells. 3. Immature neutrophils mobilized by G-CSF are larger and demonstrate increased resistance to deformation, leading to their localization in the lung. We believe the results of these experiments will provide new information on fundamental aspects of normal homeostasis as well as insights into mechanisms of neutrophil-dependent inflammatory states.