Recombinant colony stimulating factors such as granulocyte (rG-CSF) and granulocyte-macrophage colony stimulating factor (rGM-CSF) are capable of both increasing bone marrow leukocyte production as well as increasing the activity level of circulating and resident tissue cells. Administration of these factors improves survival in irradiated neutropenic animal models and decreases the frequency of infection in neutropenic patients. The use of such factors in non-neutropenic patients with sepsis has the potential to be either harmful or beneficial. We have now shown that rG-CSF pretreatment in a non-neutropenic canine model of lethal bacterial peritonitis improves cardiovascular function and survival. These improvements are associated with decreases in circulating endotoxin levels. Although rG-CSF accelerates alveolar neutrophil recruitment in this model, pulmonary injury is not worsened. In addition to reductions in circulating endotoxin levels, we have now shown that rG-CSF pretreatment reduces circulating tumor necrosis factor (TNF) levels as well. In a subsequent set of studies we evaluated the effects of rG-CSF administered at the onset of bacterial sepsis rather than prophylactically. In these studies we found that rG-CSF, despite administration at very high dosages (40 to 80 microg/kg ql2h), did not result in increased circulating neutrophil numbers and did not appear to offer a protective advantage. The absence of an increase in circulating neutrophil numbers in this study was striking. It suggested either that the marrow had become depleted of cells, or, possibly more important clinically, that during sepsis the marrow, despite adequate.cell numbers, was no longer responsive to the stimulatory effects of mediators like G-CSF. To evaluate this effect further, we plan to do serial bone marrow studies in a group of septic animals receiving rG-CSF or placebo, started at the initiation of sepsis.
