Clostridial gas gangrene. I. Cellular and molecular mechanisms of microvascular dysfunction induced by exotoxins of Clostridium perfringens

Mechanisms responsible for the rapid tissue destruction in gas gangrene are not well understood. To examine the early effects of Clostridium perfringe ns exotoxins on tissue perfusion, a rat model of muscle blood flow was deve loped. Intramuscular injection of a clostridial toxin preparation containin g both phospholipase C (PLC) and theta-toxin caused a rapid (1-2 min) and i rreversible decrease in blood how that paralleled formation of activated pl atelet aggregates in venules and arterioles. Later (20-40 min), aggregates contained fibrin and leukocytes, and neutrophils accumulated along vascular walls. Flow cytometry confirmed that these clostridial toxins or recombina nt PLC induced formation of P-selectin-positive platelet aggregates. Neutra lization of PLC activity in the clostridial toxin preparation completely ab rogated human platelet responses and reduced perfusion deficits. It is conc luded that tissue destruction in gas gangrene is related to profound attenu ation of blood how initiated by activation of platelet responses by PLC.