Pathophysiologic basis of sepsis: Considerations for future strategies of intervention

Objective: To analyze the implications for therapeutic advances in the trea tment of sepsis and septic shock based on the mechanisms underlying the res ponse to microbial infection. Data Sources: Clinical trials and experimental models designed to determine the key mechanisms involved in cellular and molecular processes of inflamm atory reactions. Study Selection: Analyses of normal immune reactions to microbial infection , processes involved in the development of sepsis, and reasons for frequent failure of regimens based on current therapeutic rationales. Data Extraction/Synthesis: Review of the data suggests that the dysregulati on of the immune system resulting in sepsis/septic shock is ineffectually b locked by interfering with the action of inflammatory mediators or cascades , as these processes may be too complex to be easily antagonized. Rather, b lockade of the action of microbial products or of the intracellular process es activated by receptor interaction with these products may provide a more promising therapeutic alternative. Conclusions: The sepsis syndrome induced by microbial pathogens reflects ex cessive stimulation of the processes of innate immunity, Bacterial componen ts reacting with specific receptors activate intracellular processes, resul ting in the release of excessive amounts of mediators of inflammation as we ll as triggering multiple complex proteolytic cascades. Blockade or antagon ism of the actions of individual intermediary messenger molecules has prove d therapeutically unsuccessful, because blockade of mediators alone does no t block the direct activation of processes such as coagulation and compleme nt. The dysregulation that characterizes sepsis may be amenable to blockade of the bacterial components or to the intracellular pathways triggered by these products.