CD-18 DEPENDENT/INDEPENDENT WBC RESPONSES IN THE LUNG

描述（由申请人提供）：根据刺激，中性粒细胞可通过至少两种不同的途径迁移到肺中，一种需要CD 11/CD 18粘附复合物，另一种不需要。 我们的研究提供了证据表明，NF-κ B p65（Rel A）亚单位缺陷的小鼠，TNF R1和IL-1 R1缺陷的小鼠，或ICAM-1阻断的小鼠在E.大肠杆菌诱导的CD 18依赖性迁移。 相反，白细胞非受体Src酪氨酸激酶林恩、Fgr和Hck、小GT3 Rac 2或干扰素-（IFN-γ）缺陷的小鼠具有S.肺炎克雷伯氏菌诱导的CD 18非依赖性，而E.大肠杆菌诱导的CD 18依赖性迁移。 此外，外源性IFN-α将依赖于CD 18的迁移转换为不依赖于CD 18的迁移，而IFN-α的遗传缺陷将不依赖于CD 18的迁移转换为依赖于CD 18的迁移。 比较这些细菌性肺炎中基因表达的研究也提供了许多新的想法。 我们的目标是了解CD 18依赖性和CD 18非依赖性粘附途径的机制，并确定调节急性炎症过程以使宿主受益的方法。 我们的工作假设是，当宿主防御的早期阶段导致NF-κ B核转位、TNF-α和IL-1的产生以及肺毛细血管内皮细胞上ICAM-1表达增加时，中性粒细胞通过CD 11/CD 18依赖性途径迁移，而当IFN-α产生并且白细胞Src激酶林恩、Fgr、并且Hck和小的GTdR ac 2被激活。 提出的目标将测试这一假设，并检查这些所需的分子中的每一个在中性粒细胞迁移机制中的作用。 目的1探讨NF-β B介导的基因转录以及TNF-α和IL-1在CD 18依赖性和非依赖性中性粒细胞迁移中的作用。 目的2将确定IFN-g在CD 18非依赖性迁移中的作用。 目的3将确定林恩、Fgr和Hck以及Rac 2的作用，以及这些分子与IFN-γ在中性粒细胞募集和功能中的功能关系。 目的4：利用基因芯片技术筛选出在大肠杆菌中差异表达的分子，并确定其功能。pneumoniae而不是E.大肠杆菌肺炎。 这些研究将有助于阐明中性粒细胞募集的分子机制，并确定潜在的治疗靶点。

DESCRIPTION (provided by applicant): Neutrophil emigration into the lungs can occur through at least two different pathways depending upon the stimulus, one that requires the CD11/CD18 adhesion complex, and one that does not. Our studies provide evidence that mice deficient in the NF-kappaB p65 (Rel A) subunit, mice deficient in both TNF R1 and IL-1R1, or mice with blockade of ICAM-1 have defects in E. coli-induced CD18-dependent emigration. In contrast, mice deficient in the leukocyte non-receptor Src tyrosine kinases Lyn, Fgr, and Hck, in the small GTPase Rac2, or in interferon-(IFN-g) have defects in S. pneumoniae-induced CD18-independent but not E. coli-induced CD18-dependent emigration. Moreover, exogenous IFN-( switches CD18-dependent to CD18-independent emigration, whereas genetic deficiency of IFN-( switches CD18-independent to CD18-dependent emigration. Studies comparing gene expression during these bacterial pneumonias also provided many new ideas. Our goal is, to understand the mechanisms, through which CD18-dependent and CD18-independent adhesion pathways are elicited and function; and to identify ways of modulating the acute inflammatory process to benefit the host. Our working hypothesis is that neutrophil emigration occurs through CD11/CD18-dependent pathways when early stages of host defense result in nuclear translocation of NF-kappaB, production of TNF-alpha and IL-1, and increased expression of ICAM-1 on pulmonary capillary endothelial cells, while CD11/CD18- independent mechanisms are selected when IFN-( is produced and the leukocyte Src kinases Lyn, Fgr, and Hck and the small GTPase Rac2 are activated. The proposed Aims will test this hypothesis and examine the role of each of these required molecules in the mechanisms of neutrophil emigration. Aim 1 will determine the role of NF-(B -mediated gene transcription and the function of TNF-alpha and IL-1 in CD18- dependent and -independent neutrophil emigration. Aim 2 will determine the role of IFN-g in CD18- independent emigration. Aim 3 will determine the role of Lyn, Fgr, and Hck and of Rac2, and the functional relationships between these molecules and IFN-g in neutrophil recruitment and function. Aim 4 will determine the functional role of molecules identified by gene microarray technology to be differentially expressed in S. pneumoniae but not E. coli pneumonia. These studies will help to elucidate the molecular mechanisms of neutrophil recruitment and identify potential targets for therapy.