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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.
AuthorsS M Opal, J W Jhung, J C Keith Jr, S J Goldman, J E Palardy, N A Parejo
JournalBlood (Blood) Vol. 93 Issue 10 Pg. 3467-72 (May 15 1999) ISSN: 0006-4971 [Print] United States
PMID10233899 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Immunosuppressive Agents
  • Interleukin-11
  • Recombinant Proteins
  • Granulocyte Colony-Stimulating Factor
  • Cyclophosphamide
Topics
  • Animals
  • Bacteremia (pathology, therapy)
  • Cyclophosphamide (pharmacology)
  • Granulocyte Colony-Stimulating Factor (administration & dosage, therapeutic use)
  • Humans
  • Immunosuppressive Agents (pharmacology)
  • Inflammation
  • Injections, Subcutaneous
  • Interleukin-11 (administration & dosage, therapeutic use)
  • Intestinal Mucosa (pathology)
  • Intestine, Small (pathology)
  • Neutropenia (complications)
  • Pseudomonas Infections (pathology, therapy)
  • Pseudomonas aeruginosa
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins (administration & dosage, therapeutic use)
  • Survival

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