Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia.
OBJECTIVE
To characterize microcirculatory actions of activated protein C in an endotoxemia rodent model that allows in vivo studies of microvascular inflammation and perfusion dysfunction.


METHODS
Animal study using intravital microscopy.


METHODS
Animal research facility.


METHODS
Male Syrian golden hamsters, 6-8 wks old with a body weight of 60-80 g.


METHODS
In skinfold preparations, endotoxemia was induced by intravenous administration of 2 mg/kg endotoxin (lipopolysaccharide, Escherichia coli). Intravital microscopy allowed quantitative analysis of arteriolar and venular leukocyte adhesion and functional capillary density (cm) that served as a measure of microvascular perfusion failure. Activated protein C (APC group, n = 8, 24 microg/kg intravenously) was substituted continuously during 8 hrs after lipopolysaccharide, whereas endotoxemic buffer-treated animals (control, n = 7) served as controls.


RESULTS
Lipopolysaccharide increased leukocyte adhesion and decreased functional capillary density to 50% of baseline values (p <.01 vs. baseline). Activated protein C treatment inhibited (p <.05) lipopolysaccharide-mediated leukocytic response and attenuated (p <.05) endotoxic perfusion failure in nutritive capillaries.


CONCLUSIONS
Activated protein C-induced protection from lipopolysaccharide-mediated microcirculatory dysfunction was characterized in vivo for the first time. The impressive modification of leukocyte cross-talk indicates systemic anti-inflammatory activated protein C effects on leukocytes and the endothelium, subsequently improving capillary perfusion. These actions could represent the in vivo mechanism of activated protein C interactions observed in patients with severe sepsis.
Hoffmann
Johannes N
JN
Department of Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany.
Vollmar
Brigitte
B
Laschke
Matthias W
MW
Inthorn
Dietrich
D
Fertmann
Jan
J
Schildberg
Friedrich W
FW
Menger
Michael D
MD
D000818:Animals; D006224:Cricetinae; D019446:Endotoxemia / Q000276:immunology*; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D007957:Leukocyte Adherence Inhibition Test; D036904:Leukocyte Rolling / Q000187:drug effects; D008070:Lipopolysaccharides; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects; D020678:Microscopic Angioscopy; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000098:blood supply*; D011486:Protein C / Q000494:pharmacology*; D012867:Skin / Q000098:blood supply*; D012884:Skin Window Technique
D008070:Lipopolysaccharides; D011486:Protein C