CD-18 DEPENDENT/INDEPENDENT WBC RESPONSES IN THE LUNG

Case Western Reserve University, Cleveland OH

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Abstract

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.