Changes in HLA-DR expression, cytokine production and coagulation following endotoxin infusion in healthy human volunteers.
The infusion of a low dose of endotoxin into healthy subjects triggers a complex inflammatory response but the intricacies of which, despite extensive research, are still being unraveled. Nine healthy male volunteers received a dose of 30 Units endotoxin/kg bodyweight as an intravenous bolus. Following endotoxin infusion the concentration of TNF-alpha in their serum rapidly increased within 30 min, peaked after 1-2 h and returned to baseline by 4 h. This corresponded to a similarly rapid increase in anti-inflammatory soluble TNF receptor (sTNFR) levels, which remained elevated for up to 48 h. Increased levels of other cytokines were measured, including IL-6, IL-8, G-CSF, IL-1ra and IL-10. However, these cytokines lagged behind that of TNF-alpha and remained elevated for up to 8 h. Endotoxin injection resulted in complex changes in HLA-DR expression, a marker of monocyte activation state. Initially, following a lag of 2-4 h, HLA-DR expression decreased with a nadir at 8 h, followed by an increase in expression above baseline at 22 h. HLA-DR levels returned to baseline 48 h post-endotoxin challenge. This was in contrast to endotoxin-induced changes in white blood cell (WBC) numbers, which dropped rapidly (at 2-3 h) while HLA-DR levels were stable and then peaked during the nadir in HLA-DR expression (8 h). Furthermore, endotoxin injection caused activation of both fibrinolytic and coagulation pathways. Thus, endotoxin infusion results in complex changes in HLA-DR expression, production of pro- and anti-inflammatory cytokines and activation of coagulation.
Mant
Timothy G K
TG
Guy's Drug Research Unit, London SE1 1YR, United Kingdom.
Borozdenkova
Svetlana
S
Bradford
Daniel B A
DB
Allen
Elizabeth
E
Amin
Dipti M
DM
Toothaker
Roger D
RD
Collins
Robert W M
RW
Hargreaves
Roseanna E G
RE
Jurcevic
Stipo
S
D000991:Antithrombins / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D002097:C-Reactive Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004562:Electrocardiography / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity*; D005342:Fibrinolysis / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006684:HLA-DR Antigens / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D008111:Liver Function Tests; D010314:Partial Thromboplastin Time
D000991:Antithrombins; D016207:Cytokines; D004731:Endotoxins; D006684:HLA-DR Antigens; D008070:Lipopolysaccharides; D016179:Granulocyte Colony-Stimulating Factor; C044101:endotoxin, Escherichia coli; D002097:C-Reactive Protein