In severe burns with sepsis, granulocyte production is arrested despite elevated levels of the primary granulopoietic growth factor, granulocyte colony-stimulating factor (G-CSF). The inability of granulocytic cells to respond to G-CSF may be a a consequence of G-CSF receptor down regulation in these cells. While bone marrow (BM) myeloid G-CSF receptor status in vivo is unknown, in vitro studies have demonstrated that bioactive products released as the result of bacterial infection and massive tissue injury (e.g., LPS and TNF-2) can down regulate G-CSF receptors on immatue myeloid cells and neutrophils. Accordingly, the investigator hypothesizes that G-CSF receptor on myeloid cells of the granulocytic lineage is down regulated in burn sepsis leading to impairred granulocyte production. This hypothesis will be tested in murine burn / Pseudomonas aeruginosa sepsis model.
Four specific aims will be addressed.
The first aim i s to demonstrate the down regulation of G-CSF receptor density in bone marrow cells in burned/infected mice as specific times after injury.
The second aim i s to determine the stage(s) in the development of bone marrow myeoloid cells where maturation is impaired and where G-CSF receptors are down regulated.
The third aim i s to evaluate the ability of PGE2, a recognized mediator of burn-induced immunosuppression, on G-CSF receptor expression on murine myeloid cells (NFS-60 and 32Dc13) in vitro.
The fourth aim i s to determine whether burn/sepsis bone marrow myelosuppression and G-CSF receptor down regulation can be ameliorated by blocking PGE2 production or activity, with indomethacin (a nonspecific COX inhibitor), SC19920 (a selective PGE2 receptor antagonist), or SC-236 (a specific COX-2 inhibitor).
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