Neutrophil Homeostasis and Lung Sequestration

描述（由申请人提供）：中性粒细胞在炎症反应中的产生、释放和处理仍然知之甚少。许多嗜中性粒细胞依赖的肺部疾病，包括成人呼吸窘迫综合征（ARDS），其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衍生的体外系统，以及小鼠和人体外细胞，我们提出验证相互关联的假设，以探索白细胞增多和肺隔离的基本机制。1. 炎症期间，TNF和其他细胞酶诱导G-CSF的全身性表达。G-CSF不仅增加了祖细胞的数量，而且延缓了发育中的中性粒细胞的凋亡，从而增加了中性粒细胞的产生。2. G-CSF通过三个系统的修饰来动员未成熟的中性粒细胞：SDF-1对CXCR4的信号传导，唾液粘附素与其配体的相互作用，以及ALCAM在基质细胞和造血细胞上的同型相互作用。3. 被G-CSF动员的未成熟中性粒细胞更大，对变形的抵抗力增强，导致它们在肺中的定位。我们相信这些实验的结果将提供关于正常体内平衡基本方面的新信息，以及对中性粒细胞依赖性炎症状态机制的见解。

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.