Recombinant human
granulocyte colony-stimulating factor (rhG-CSF) is widely used to promote granulocyte recovery from a variety of pathologic states. Recombinant human
interleukin-11 (rhIL-11) has recently become available clinically as a platelet restorative agent after myelosuppressive
chemotherapy. Preclinical data has shown that
rhIL-11 limits mucosal injury after
chemotherapy and attenuates the proinflammatory
cytokine response. The potential efficacy of combination
therapy with recombinant human forms of
rhIL-11 and rhG-CSF was studied in a neutropenic rat model of Pseudomonas aeruginosa
sepsis. At the onset of
neutropenia, animals were randomly assigned to receive either rhG-CSF at a dose of 200 micrograms/kg subcutaneously every 24 hours for 7 days;
rhIL-11 at 200 micrograms/kg subcutaneously every 24 hours for 7 days; the combination of both rhG-CSF and rhIL-11; or saline control. Animals were orally colonized with Pseudomonas aeruginosa 12.4.4 and then given a myelosuppressive dose of
cyclophosphamide. rhG-CSF resulted in a slight increase in absolute neutrophil counts (ANC), but did not provide a survival advantage (0 of 12, 0% survival) compared with the placebo group (1 of 12, 8% survival).
rhIL-11 was partially protective (4 of 10, 40% survival); the combination of rhG-CSF and
rhIL-11 resulted in a survival rate of 80% (16 of 20; P <.001).
rhIL-11 alone or in combination with rhG-CSF resulted in preservation of gastrointestinal mucosal integrity (P <.001), lower circulating
endotoxin levels (P <.01), and reduced quantitative levels of P. aeruginosa in quantitative organ cultures. These results indicate that the combination of
rhIL-11 and rhG-CSF is additive as a treatment strategy in the prevention and treatment of experimental Gram-negative
sepsis in immunocompromised animals. This combination may prove to be efficacious in the prevention of
severe sepsis in neutropenic patients.