Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB.
OBJECTIVE
To review the anti-inflammatory and anti-apoptotic properties of drotrecogin alfa (activated) (recombinant human activated protein C), emphasizing its modulatory effects on endothelial nuclear factor-kappaB. We propose a broad anti-inflammatory effect of drotrecogin alfa (activated), acting on both endothelium and monocytes.


METHODS
A selected review of the published literature on nuclear factor-kappaB, severe sepsis, and the use of drotrecogin alfa (activated) in clinical and preclinical models, together with data derived from preclinical gene profiling of model systems.


METHODS
Data from the PROWESS trial support the preclinical evidence of an antithrombotic effect of drotrecogin alfa (activated). Anti-inflammatory effects through reduction of thrombin generation and through thrombin-independent mechanisms in mononuclear and endothelial cells are reviewed. Inhibition of apoptosis is used as an example of the protective effect of drotrecogin alfa (activated) on endothelial and mononuclear cell dysfunction.


CONCLUSIONS
Drotrecogin alfa (activated) acts as a modulator of nuclear factor-kappaB to aid in the host immune response in endothelium and monocytes. Extrapolation of gene array findings to explain apoptosis in endothelium and monocytes, coupled with emerging preclinical reports, provides evidence to support the role of drotrecogin alfa (activated) in modulating nuclear factor-kappaB.
Joyce
David E
DE
Division of Clinical Research, Lilly Research Laboratories, Indianapolis, IN, USA. joyce_david_e@lilly.com
Grinnell
Brian W
BW
D017304:Annexin A5 / Q000187:drug effects; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D009000:Monocytes / Q000187:drug effects*; D016328:NF-kappa B / Q000187:drug effects*; D011486:Protein C / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology*
D017304:Annexin A5; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011486:Protein C; D011994:Recombinant Proteins; C421124:drotrecogin alfa activated