Complement and tumor necrosis factor-alpha contribute to Mac-1 (CD11b/CD18) up-regulation and systemic neutrophil activation during endotoxemia in vivo.
The increased expression of Mac-1 (CD11b/CD18) adhesion glycoproteins on neutrophils was studied using flow cytometry in male Fischer 344 rats treated with 5 mg/kg Salmonella enteritidis endotoxin. A rapid and sustained threefold increase of Mac-1 expression was observed after endotoxin injection. Inhibition of complement activation with the soluble complement receptor type 1 (sCR1) completely suppressed the initial up-regulation of Mac-1 (< or = 15 min) but did not prevent the activation during the later phase (30-90 min). During that time period, Mac-1 expression increased in parallel with the concentration of tumor necrosis factor alpha (TNF-alpha) in plasma and could be significantly attenuated with TNF antiserum. To verify the results, isolated human neutrophils were incubated with rat plasma obtained at various times after endotoxin injection. Using shape change as indicator of neutrophil activation, complement and TNF-alpha could be identified as responsible mediators for neutrophil activation during endotoxemia in vivo. In contrast, the massive neutrophil accumulation in the liver after endotoxin was only slightly reduced by sCR1 and unaffected by TNF antiserum. It is concluded that Mac-1 up-regulation on neutrophils after endotoxin injection in vivo may have limited relevance for hepatic neutrophil infiltration but may be important for the pathogenesis of endotoxin-induced liver injury by facilitating adherence-dependent neutrophil cytotoxicity.
Witthaut
R
R
Department of Medicine, Baylor College of Medicine, Houston, Texas.
Farhood
A
A
Smith
C W
CW
Jaeschke
H
H
D000818:Animals; D003165:Complement System Proteins / Q000502:physiology*; D004731:Endotoxins / Q000097:blood*; D006801:Humans; D016177:Macrophage-1 Antigen / Q000032:analysis*; D008297:Male; D009504:Neutrophils / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D012477:Salmonella enteritidis / Q000472:pathogenicity; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D004731:Endotoxins; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins