Neurtophil Homeostasis and Lung Sequestration

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DESCRIPTION (provided by applicant): The release of neutrophils from the marrow in response to inflammation remain 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. We propose to test interrelated hypotheses that explore fundamental mechanisms of neutrophil release in response to lung inflammation. Using a novel in vitro marrow culture system developed in the previous grant period, new approaches to conditional immortalization and capture of specific developmental stages, in vitro microscopy of marrow and in vivo trafficking of neutrophils in the mouse, we will (1) Determine the mechanisms by which alterations in adhesive state of a4¿1 regulates release of neutrophils from marrow during homeostasis, as we hypothesize that adhesion through a4¿1 restrains release of a subset of neutrophils primed for release, (2) Determine the mechanisms by which the adhesive state of a4¿1 regulates release of neutrophils from marrow during inflammation, hypothesizing that regulation of adhesion through a4¿1 is necessary for accelerated release of less-mature cells that must migrate to the vasculature under the influence of CXCR2 ligands. (3) Test the hypothesis that release of neutrophils during inflammation requires the coordinated action of CXCL12/CXCR4, CXCL5/CXCR2, and S1P/S1P receptor(s), with the hypothesis that down-regulation of signaling through CXCR4 by CXCL5 acting through CXCR2 permits release of cells, while S1P enhances migration towards the vasculature induced by CXCR2 ligands such as CXCL5. These studies should reveal mechanisms by which the release of neutrophils in response to an inflammatory response in the lung is regulated, and provide new targets for not only improving host defense, but also minimizing tissue injury.