COMPARISON OF PERIPHERAL-BLOOD LEUKOCYTE KINETICS AFTER LIVE ESCHERICHIA-COLI, ENDOTOXIN, OR INTERLEUKIN-1-ALPHA ADMINISTRATION - STUDIES USING A NOVEL INTERLEUKIN-1 RECEPTOR ANTAGONIST

Objective This study was undertaken to evaluate whether hematologic an d immunologic effects observed after bacteremia and endotoxemia in the host could be replicated by administration of recombinant human inter leukin-1alpha (IL-1alpha) in a primate model. Furthermore, to determin e whether endogenously produced interleukin-1 (IL-1) contributes to th e changes observed during endotoxemia or gram-negative septic shock, a specific IL-1 receptor antagonist (IL-1ra) was administered. Summary Background Data The lipopolysaccharide (LPS) component of the outer me mbrane of gram-negative bacteria initiates a constellation of metaboli c and immunologic host responses. IL-1, a macrophage-derived cytokine, acts as a key mediator in the host response to infection and inflamma tion. Methods Baboons were randomly assigned to receive either recombi nant human IL-1alpha, LPS, or live Escherichia coli both with or witho ut concomitant administration of IL-1ra. Blood was collected hourly an d 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, bu t was sustained in the bacteremic group. An early lymphopenia and mono cytopenia was elicited by LPS or E. coli and persisted throughout the experiment. Recombinant human IL-1alpha induced the following: (1) an early, transient decline in granulocytes followed by a sustained granu locytosis; (2) a lymphopenia; and (3) a transient monocytopenia follow ed by a gradual return to baseline. Although IL-1ra had no effect on l eukocyte kinetics with either live E. coli or LPS, the IL-1ra signific antly abrogated the monocytopenia seen with recombinant human IL-1alph a administration alone. Conclusions These results suggest that adminis tration of recombinant human IL-1alpha can replicate some of the chara cteristic patterns of hematologic change associated with bacteremia an d endotoxemia. However, an endogenous IL-1 response is not required fo r these changes to occur. Rather, the data suggest that other inflamma tory mediators induced by endotoxemia or gram-negative bacteremia, suc h as tumor necrosis factor-alpha (TNFalpha), may be involved.