Multi-cellular activation in vivo by endotoxin in humans--limited protection by adenosine infusion.
The influence of adenosine infusion (40 microg/kg/min for 4 h) on inflammatory and hemostatic parameters was investigated in healthy males without (n = 10) or with (n = 11) intravenous endotoxin injection (4 ng/kg). Without endotoxin, adenosine elevated circulating leukocytes and circulating platelet-leukocyte aggregates. Endotoxin activated platelets and leukocytes in vivo. Platelet activation was seen as slightly increased platelet P-selectin expression, decreased platelet counts, and elevated plasma soluble P-selectin (from 39.6 +/- 3.4 to 68.9 +/- 6.6 ng/ml, P<0.01). Leukocyte activation was evidenced by increased CD1 lb expression (from MFI of 0.54 +/- 0.02 to 2.21 +/- 0.17; P<0.01) and plasma elastase levels (from 25.3 +/- 2.5 to 169.3 +/- 22.5 ng/ml: P <0.01). Endotoxin also enhanced platelet and leukocyte responsiveness to in vitro stimulation. Endotoxin induced von Willebrand factor secretion (from 92 +/- 8 units to 265 +/- 19 units at 4 h; P <0.001) and enhanced thrombin generation in vivo. Endotoxin induced leukocytosis and thus increased circulating platelet-leukocyte, mainly platelet-neutrophil, aggregates. Adenosine caused slight attenuation of platelet reactivity to agonist stimulation, enhanced the endotoxin-induced leukocytosis, and detained more platelet-leukocyte aggregates in circulation, but did not attenuate endotoxin-induced neutrophil elastase secretion, von Willebrand factor secretion, or thrombin generation. Thus, endotoxemia induces multi-cellular activation in vivo. Adenosine inhibits leukocyte adhesion and extravasation, and mildly attenuates platelet responsiveness and soluble P-selectin release. Adenosine has the potential of becoming a therapeutic antiinflammatory drug, but an optimal treatment strategy needs to be developed.
Li
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N
Department of Medicine, Karolinska Hospital, Stockholm, Sweden.
Soop
A
A
Sollevi
A
A
Hjemdahl
P
P
D000241:Adenosine / Q000008:administration & dosage* / Q000494:pharmacology; D000328:Adult; D002448:Cell Adhesion / Q000187:drug effects; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004731:Endotoxins / Q000494:pharmacology*; D006403:Hematologic Tests; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation; D007262:Infusions, Intravenous; D007962:Leukocytes / Q000187:drug effects; D016177:Macrophage-1 Antigen / Q000097:blood / Q000187:drug effects; D008297:Male; D019007:P-Selectin / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000097:blood / Q000187:drug effects; D010919:Placebos / Q000008:administration & dosage; D015539:Platelet Activation / Q000187:drug effects*; D011516:Prothrombin / Q000187:drug effects; D014841:von Willebrand Factor / Q000187:drug effects / Q000378:metabolism
D004731:Endotoxins; D016177:Macrophage-1 Antigen; D019007:P-Selectin; D010446:Peptide Fragments; D010919:Placebos; C045879:prothrombin fragment 1.2; D014841:von Willebrand Factor; D011516:Prothrombin; D000241:Adenosine