CD-18 DEPENDENT/INDEPENDENT WBC RESPONSES IN THE LUNG

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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.