Objective: Severe sepsis remains the dominant challenge in the care of critically ill patients. Over the last 10 years a large body of research has modified our understanding of this condition. In this article, we review the evolution of our understanding of the molecular mechanisms responsible for the development of this clinical syndrome.
Data sources: The authors undertook a critical review of the literature on the molecular basis of the pathogenesis of sepsis with particular emphasis on the role of cytokines, toll-like receptors, adhesion molecules, coagulation cascade molecules and the possible role of in-vitro experimental models of blood-endothelium interaction.
Summary of review: Recent insights into the molecular mechanisms responsible for the pathogenesis of the severe sepsis syndrome suggest that pro- and anti- inflammatory pathways are simultaneously activated and interact in a dynamic way. Pro-inflammatory cytokines previously considered as targets for intervention have typically been already activated and de-activated by the time the clinical diagnosis is made and intervention is possible. Cellular activity involving white cell-endothelial interactions occur later, making them a more attractive option for therapeutic intervention. Immunological incompetence rather than over-activity may be the most common state of cell function in critically ill patients.
Conclusions: Our understanding of the the pathogenesis of severe sepsis continues to grow. Expression of membrane surface molecules such as toll-like receptors, adhesion molecules and cytokine receptors induce a high degree of redundancy and amplification. Cell responsiveness is reduced in an attempt to circumvent the amplification loop. However, the ensuing interaction between the host and the pathogen(s) may lead to an immune deficiency, leaving the field open to further invasion by the original bacteria or to superimposed infection agents. Endothelium-white cell interactions might be an appropriate target for future interventions.