Activated protein C improves the visceral microcirculation by attenuating the leukocyte-endothelial interaction in a rat lipopolysaccharide model.
OBJECTIVE
Abnormalities in the vascular endothelial function play an important role in the development of septic organ dysfunction. The aim of the study was to examine the effect of recombinant human activated protein C on leukocyte-endothelial interaction in endotoxemia.


METHODS
Experimental animal model of sepsis.


METHODS
University research laboratory.


METHODS
Normal Wistar rats. Each animal was infused with 4.5 mg/kg lipopolysaccharide to simulate severe sepsis.


METHODS
Rats were injected with endotoxin simultaneously with either a low or a high dose of recombinant human activated protein C (n = 7). One, 2, and 3 hrs after injection, mesenteric microcirculation was observed under intravital microscopy. In another series, tumor necrosis factor, interleukin-6, alanine transaminase, and blood urea nitrogen levels were evaluated (n = 5).


RESULTS
The adhesive leukocyte count on the endothelium was significantly suppressed in both high-dose and low-dose groups (p < .01 and .05, respectively). The bleeding events decreased in the low-dose treatment group compared with both the control (p < .05) and high-dose group (p < .05). Microcirculatory flow as expressed by red blood cell velocity was maintained better in the low-dose group. Comparison of cytokine levels showed a significant decrease in the treatment groups. Organ damage markers were also suppressed in the treatment groups (p < .05)


CONCLUSIONS
Recombinant human activated protein C demonstrated a protective effect on microcirculation through the inhibition of leukocyte-endothelial interaction and suppression of inflammatory cytokine production.
Iba
Toshiaki
T
Department of Surgery, Juntendo Urayasu Hospital, Juntendo University School of Medicine, Urayasu, Chiba, Japan.
Kidokoro
Akio
A
Fukunaga
Masaki
M
Nagakari
Kunihiko
K
Shirahama
Akihiko
A
Ida
Yukiko
Y
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001783:Blood Flow Velocity; D002448:Cell Adhesion; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D004926:Escherichia coli; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008070:Lipopolysaccharides; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D010976:Platelet Count; D011486:Protein C / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D018805:Sepsis / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D013152:Splanchnic Circulation / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000925:Anticoagulants; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011486:Protein C; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase