Activated recombinant human protein C does not attenuate recruitment of neutrophils in rat models of acute inflammation.
It has been proposed that the reduction in mortality in animal models of sepsis by activated protein C (APC) is mediated by an antiinflammatory property rather than the well-characterized anticoagulant action. Human recombinant APC was examined for potential antiinflammatory activity in the pentobarbital-anesthetized rat. In the dermal reversed passive Arthus model, APC (20.0 mg/kg/h, i.v.) elevated clotting time 10-fold 3 h after the Arthus challenge, at which time, the wet-weights from Arthus dermal samples in APC rats (120.0 +/- 1.5 mg, n = 10) did not differ from controls (120.1 +/- 1.5 mg, n = 10) but were 30% heavier than remote noninflamed skin (92.0 +/- 2.0 mg, n = 10), indicating that APC treatment did not diminish tissue edema associated with immune-complex deposition. Skin-lesion myeloperoxidase (neutrophil marker enzyme) activities from APC rats were not significantly different from controls but was 21-fold more than remote noninflamed skin, indicating that APC treatment did not diminish dermal recruitment of neutrophils. In the intestinal ischemia/reperfusion model, 1 h complete occlusion of the superior mesenteric artery and an additional 4 h reperfusion was associated with a 2.87-fold increase in lung myeloperoxidase activity compared to sham-operated rats. APC (1.0 mg/kg/h, i.v.) did not diminish the elevation in this index of lung neutrophil sequestration. In conclusion, APC did not produce an antiinflammatory effect in the rat models used.
O'Leary
E C
EC
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.
Schelm
J A
JA
Simpson
P J
PJ
D000208:Acute Disease; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001183:Arthus Reaction / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D007249:Inflammation / Q000097:blood / Q000188:drug therapy; D007422:Intestines / Q000098:blood supply; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010314:Partial Thromboplastin Time; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011486:Protein C; D011994:Recombinant Proteins; D009195:Peroxidase