Granulocytes are critical constituents of host defense against bacterial invasion and an inadequate production of granulocytes invariably results in lifethreatening infection. Infection accounts for 75% of all deaths following burn injury, and septicemia with a mortality rate approaching 75% is the most common type of infection. Recent data from our laboratory suggest that a defect(s) in the regulation of granulocyte production may be responsible for the high incidence of fatal septicemia in severely burned humans. Monocyte production of colony-stimulating factor (CSF), a factor necessary for the proliferation and maturation of granulocyte precursors, is depressed, serum levels of CSF are low, and granulocyte stem cells grown in soft agar culture (CFU-C) are reduced in burned patients who ultimately develop overwhelming sepsis and die. In contrast, burned patients who survive sepsis or never become septic have normal or elevated CSF production and CFU-C proliferation. We believe that the defect in CSF production and stem cell proliferation may be due to overproduction of negative feedback regulators of granulopoiesis such as lactoferrin (LF), a known modulator of CSF production, and prostaglandin E2 (PGE2) or acidic isoferritin (AIF), known inhibitors of granulocyte stem cell proliferation. Confirming a pathophysiologic role for such counter regulators of postburn granulopoiesis is important, because their effects can be reversed with drugs now clinically available such as lithium and indomethacin. In this proposal, we will correlate the peripheral blood mononuclear cell (MNC) production of granulocyte stimulatory (CSF) and inhibitory (PGE2 and AIF) factors with granulocyte stem cells proliferation by performing in vitro soft agar culture techniques never before performed in burned humans. Also, the modulating effects of blood CSF, LF, and bacterial lipopolysaccharide (LPS) levels and of monocyte and lymphocyte subpopulations on CSF production and stem cell proliferation will be assessed. Such information will provide new insights into postburn granulopoiesis and enable us to construct a unifying concept of postburn granulopoiesis which will allow a more rational approach to bolstering host granulocyte defense against infection. This knowledge can then be used to reduce the incidence and/or severity of infection following major thermal injury in humans.
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| Peterson, V M; Murphy, J R; Haddix, T et al. (1988) Identification of novel prognostic indicators in burned patients. J Trauma 28:632-7 |
| Stork, L C; Peterson, V M; Rundus, C H et al. (1988) Interleukin-1 enhances murine granulopoiesis in vivo. Exp Hematol 16:163-7 |
| Iyengar, V G; Peterson, V M; Rundus, C et al. (1986) Postburn serum inhibits in vitro production of colony-stimulating factor by mononuclear peripheral blood cells. Int J Cell Cloning 4:472-82 |
