CD-18 DEPENDENT/INDEPENDENT WBC RESPONSES IN THE LUNG

描述：肺内急性中性粒细胞移出发生在 至少两种粘附途径，一种需要CD 11/CD 18，另一种需要CD 11/CD 18。 没有 选择哪条通路似乎取决于刺激 以及它诱导的细胞因子和信号因子。 此外该 由特定刺激利用的粘附途径在 复发性或慢性炎症。 该提案调查了 决定将利用哪种粘附途径以及 嗜中性粒细胞-内皮细胞和嗜中性粒细胞-基质分子相互作用 介导CD 11/CD 18非依赖性中性粒细胞迁移。 工作 假设是：1）信号转导途径和细胞因子 响应于特定刺激而诱导的粘附决定了 途径，和2）CD 18非依赖性粘附介导 通过VLA-4/VCAM-1、PECAM-1和/或中性粒细胞基质相互作用 需要β 1和β 3整联蛋白。目标1将决定 转录因子在粘附途径选择中的作用 NF-kB、AP-1和NFAT的核转位和功能 E. coli和P. 铜绿假单胞菌诱导的CD 11/CD 18非依赖性迁移相比。 pneumoniae或S.金黄色。 在目标2中，细胞因子的作用，特别是 TNF-α和IFN-g似乎在肿瘤细胞中差异表达， CD 11/CD 18依赖性和非依赖性迁移，将使用 缺乏单一和多种细胞因子或受体的小鼠，以及 可溶性抑制剂 阻断差异表达的 细胞因子改变了迁移过程中使用的粘附途径， 测定 目的3将确定VLA-4/VCAM-1粘附的作用 CD 11/CD 18依赖性和非依赖性细胞迁移中PECAM-1与细胞外基质的关系 使用几种方法，包括功能性VCAM-1缺陷的小鼠， 和PECAM-1，反义寡核苷酸，VLA-4的阻断抗体， PECAM-1和可溶性抑制剂。 急性、复发和慢性 将检查炎症。 目标4将确定双和 中性粒细胞迁移中的三细胞内皮细胞连接 毛细血管和β 1和β 3整合素在中性粒细胞- 内皮和基质相互作用。 这些研究将有助于 阐明调节中性粒细胞反应的机制， 肺部炎症

DESCRIPTION: Acute neutrophil emigration in the lungs occurs through at least two adhesion pathways, one that requires CD11/CD18 and one that does not. Which pathway is selected appears to be determined by the stimulus and which cytokines and signaling factors it induces. In addition, the adhesion pathway utilized by a particular stimulus changes during recurrent or chronic inflammation. This proposal investigates the mechanisms that determine which adhesion pathway will be utilized and what neutrophil-endothelial and neutrophil-matrix molecular interactions mediate CD11/CD18-independent neutrophil emigration. The working hypothesis is that 1) the signal transduction pathways and the cytokines induced in response to a particular stimulus determine which adhesion pathway will be utilized, and 2) CD18-independent adhesion is mediated through VLA-4/VCAM-1, PECAM-1, and/or neutrophil matrix interactions requiring beta1 and beta3 integrins. Aim 1 will determine the role of transcription factors in the selection of adhesion pathways by examining the nuclear translocation and the function of NF-kB, AP-1, and NFAT during CD11/CD18-dependent neutrophil emigration induced by E. coli and P. aeruginosa compared with CD11/CD18-independent emigration induced by S. pneumoniae or S. aureus. In Aim 2, the roles of cytokines, particularly TNF-alpha and IFN-g which appear to be differentially expressed in CD11/CD18-dependent and -independent emigration, will be examined using mice deficient in single and multiple cytokines or receptors, as well as soluble inhibitors. Whether blockade of differentially-expressed cytokines alters the adhesion pathway used during emigration will also be determined. Aim 3 will determine the roles of the VLA-4/VCAM-1 adhesion pathway and PECAM-1 in CD11/CD18-dependent and -independent emigration using several approaches, including mice deficient in functional VCAM-1 and PECAM-1, antisense oligonucleotides, blocking antibodies to VLA-4 and PECAM-1, and soluble inhibitors. Acute, recurrent, and chronic inflammation will be examined. Aim 4 will determine the roles of bi- and tri-cellular endothelial cell junctions in neutrophil emigration within capillaries and the roles of beta1 and beta3 integrins in neutrophil- endothelial and -matrix interactions. These studies will help to elucidate the mechanisms regulating the response of neutrophils during lung inflammation.