Additive effects of human recombinant interleukin-11 and granulocyte colony-stimulating factor in experimental gram-negative sepsis

Abstract

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.