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.
Hoffmann
Johannes N
JN
Department of Surgery, Klinikum Grosshadern, University of Munich, Munich, Germany. Johannes.Hoffmann@med.uni-muenchen.de
Vollmar
Brigitte
B
Laschke
Matthias W
MW
Fertmann
Jan M
JM
Jauch
Karl-Walter
KW
Menger
Michael D
MD
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000098:blood supply; D008833:Microcirculation / Q000187:drug effects*; D011486:Protein C / Q000627:therapeutic use*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D011486:Protein C; D013917:Thrombin