Septic shock by gram-negative infections: role of outer membrane proteins

The magnitude of septic shock as a clinical problem is often understated. Despite advances in our ability to diagnose and treat infectious diseases, severe sepsis leading to shock due to gram-negative infections remains one of the leading causes of mortality worldwide. Septic shock develops because of a disregulation in the host response, and the mechanisms initially recruited to fight infection produce life-threatening tissue damage and death. Recent research has witnessed a significant increase in our understanding of host-pathogen interactions, particularly in the area of innate immunity and the molecular recognition of gram-positive and gram-negative bacteria. Important new mediators of sepsis and novel mechanisms of host-cell toxicity have been identified and, together with clinical trials targeting pathways considered central to sepsis pathogenesis, provide new insight into the molecular and cellular basis of sepsis for the formulation of new strategies of intervention. Research on septic shock pathogenesis by gram-negative bacteria is mainly focused on the understanding of the molecular and cellular role played by lipopolysaccharide (LPS). Strong experimental evidence and clinical observations suggest that the release of proinflammatory cytokine mediators by LPS-responsive cells (mainly macrophages, endothelial cells and neutrophils) in response to toxic products sets in motion the genetic and physiologic program that manifests as shock. The best characterized of these toxic components is LPS, which is considered as a paradigm for other less well-characterized toxic microbial molecules. The immune protection stimulated by highly purified LPS in animals does not resolve the symptomatology of septic shock, while LPS mixed to outer membrane proteins shows a better protective activity. Several studies evidence the major role played by outer membrane proteins in the molecular interaction between the host cell and the gram-negative bacteria. Endotoxin-associated proteins consist of a complex of several major proteins that are intimately associated with the LPS. Very little is known about release of non-LPS gramnegative outer membrane components such as OMPs in sepsis. Among the OMPs, porins have been shown to play an important role in pathogenesis of bacterial infections. Porins were pyrogenic in rabbits and elicited a localized reaction when used as the sensiting and eliciting agent. Porins were also shown to kill D-galactosamine sensitized LPS-responsive and LPS-unresponsive mice. Treatment of Human Umbilical Vein Endothelial Cells: (HUVEC) with porins increased the transmigration of different leukocyte populations, inparticular of neutrophils. Porins by several gram-negative bacteria induce cytokine release by human leukocytes as well as enhancement of cytokine gene expression. Also, other components of the bacterial envelope are important in the induction and pathogenesis of septic shock such as bacterial lipoproteins (LP). As anti-LPS therapies does not seem to improve by the addition of proteins from the outer membrane or small fragments of these proteins, a great alternative to existing strategies will involve the blockage of signal transduction pathways, cytokine and inflammatory mechanisms.