Antagonists of Platelet-Activating Factor as Potential Therapeutic Agents in Shock

Summary

Shock, sepsis and trauma are conditions which can often prove life-threatening. Although the cause and evolution of these conditions may be different, in all cases the final underlying pathology consists of endothelial injury, excessive blood cell infiltration and vascular leakage. Hence, many types of shock and trauma are characterized by hemodynamic alterations and edema formation. Among the various mediators implicated in shock conditions, there is much evidence to suggest that, together with various cytokines, leukotrienes, thromboxane and proteases, the inflammatory and chemotactic autacoid, platelet-activating factor (PAF), plays an important role. Indeed, studies on several animal models have shown that infusion of PAF mimicks the shock state, that markedly increased levels of PAF are produced in shock and that PAF antagonists afford significant protection against diverse forms of shock. The precise mechanism by which PAF antagonists protect against shock conditions remains unclear, however, it is becoming apparent that in shock a complex interaction occurs between PAF, proteases and cytokines, which if uncontrolled, leads to circulatory collapse. We propose that PAF antagonists may be effective in counteracting shock and sepsis because of their indirect anti-protease activity and their ability to inhibit deleterious PAF/cytokine auto-generated feedback processes.