title: Comparison of peripheral blood leukocyte kinetics after live Escherichia coli, endotoxin, or interleukin-1 alpha administration. Studies using a novel interleukin-1 receptor antagonist.
abstract: OBJECTIVE
  This study was undertaken to evaluate whether hematologic and immunologic effects observed after bacteremia and endotoxemia in the host could be replicated by administration of recombinant human interleukin-1 alpha (IL-1 alpha) in a primate model. Furthermore, to determine whether endogenously produced interleukin-1 (IL-1) contributes to the changes observed during endotoxemia or gram-negative septic shock, a specific IL-1 receptor antagonist (IL-1 ra) was administered.
  
  
  BACKGROUND
  The lipopolysaccharide (LPS) component of the outer membrane of gram-negative bacteria initiates a constellation of metabolic and immunologic host responses. IL-1, a macrophage-derived cytokine, acts as a key mediator in the host response to infection and inflammation.
  
  
  METHODS
  Baboons were randomly assigned to receive either recombinant human IL-1 alpha, LPS, or live Escherichia coli both with or without concomitant administration of IL-1ra. Blood was collected hourly and analyzed using flow cytometric techniques.
  
  
  RESULTS
  Both endotoxemia and live E. coli bacteremia induced an acute granulocytopenia; however, the granulocytopenia gradually resolved in the endotoxemic group, but was sustained in the bacteremic group. An early lymphopenia and monocytopenia was elicited by LPS or E. coli and persisted throughout the experiment. Recombinant human IL-1 alpha induced the following: (1) an early, transient decline in granulocytes followed by a sustained granulocytosis; (2) a lymphopenia; and (3) a transient monocytopenia followed by a gradual return to baseline. Although IL-1ra had no effect on leukocyte kinetics with either live E. coli or LPS, the IL-1ra significantly abrogated the monocytopenia seen with recombinant human IL-1 alpha administration alone.
  
  
  CONCLUSIONS
  These results suggest that administration of recombinant human IL-1 alpha can replicate some of the characteristic patterns of hematologic change associated with bacteremia and endotoxemia. However, an endogenous IL-1 response is not required for these changes to occur. Rather, the data suggest that other inflammatory mediators induced by endotoxemia or gram-negative bacteremia, such as tumor necrosis factor-alpha (TNF alpha), may be involved.
authors.affiliation: Department of Surgery, Cornell University Medical College, New York, New York.
authors.forename: A S
authors.initials: AS
authors.lastname: Hawes
authors.forename: E
authors.initials: E
authors.lastname: Fischer
authors.forename: M A
authors.initials: MA
authors.lastname: Marano
authors.forename: K J
authors.initials: KJ
authors.lastname: Van Zee
authors.forename: C S
authors.initials: CS
authors.lastname: Rock
authors.forename: S F
authors.initials: SF
authors.lastname: Lowry
authors.forename: S E
authors.initials: SE
authors.lastname: Calvano
authors.forename: L L
authors.initials: LL
authors.lastname: Moldawer
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000097:blood / Q000276:immunology; D002455:Cell Division; D004731:Endotoxins / Q000008:administration & dosage / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology*; D005260:Female; D006098:Granulocytes / Q000166:cytology / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000008:administration & dosage / Q000276:immunology*; D007700:Kinetics; D007962:Leukocytes / Q000166:cytology / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D010215:Papio; D011897:Random Allocation; D012795:Sialoglycoproteins / Q000276:immunology; D014115:Toxemia / Q000097:blood / Q000276:immunology
chemical_list: D004731:Endotoxins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012795:Sialoglycoproteins