Microcirculatory alterations in ischemia-reperfusion injury and sepsis: effects of activated protein C and thrombin inhibition

Experimental studies in ischemia-reperfusion and sepsis indicate
that activated protein C (APC) has direct anti-inflammatory effects
at a cellular level. In vivo, however, the mechanisms of action
have not been characterized thus far. Intravital multifluorescence
microscopy represents an elegant way of studying the effect of APC
on endotoxin-induced leukocyte-endothelial-cell interaction and
nutritive capillary perfusion failure. These studies have clarified
that APC effectively reduces leukocyte rolling and leukocyte firm
adhesion in systemic endotoxemia. Protection from leukocytic
inflammation is probably mediated by a modulation of adhesion
molecule expression on the surface of leukocytes and endothelial
cells. Of interest, the action of APC and antithrombin in
endotoxin-induced leukocyte-endothelial-cell interaction differs in
that APC inhibits both rolling and subsequent firm adhesion,
whereas antithrombin exclusively reduces the firm adhesion step.
The biological significance of this differential regulation of
inflammation remains unclear, since both proteins are capable of
reducing sepsis-induced capillary perfusion failure. To elucidate
whether the action of APC and antithrombin is mediated by
inhibition of thrombin, the specific thrombin inhibitor hirudin has
been examined in a sepsis microcirculation model. Strikingly,
hirudin was not capable of protecting from sepsis-induced
microcirculatory dysfunction, but induced a further increase of
leukocyte-endothelial-cell interactions and aggravated capillary
perfusion failure when compared with nontreated controls. Thus, the
action of APC on the microcirculatory level in systemic endotoxemia
is unlikely to be caused by a thrombin inhibition-associated
anticoagulatory action.