Prevention and Treatment of Multiple Organ Dysfunction Syndrome: Lessons Learned and Future Prospects

Abstract

Gram-negative bacteria commonly cause serious infections in hospitalized patients, and those that lead to bacteremic episodes and sepsis syndrome are associated with the highest mortality rate. Sepsis syndrome frequently progresses to multisystem organ dysfunction and failure, with as many as 400,000 cases occurring annually. Unfortunately, the associated mortality rate remains about 40%. Lipopolysaccharide (LPS, endotoxin), an integral component of the gram-negative bacterial outer membrane, plays a critical role in the pathophysiology of this lethal disease process. It is capable of interacting with host macrophages, a process that leads to the secretion of an increasingly well-characterized array of macrophage cytokines. Several different classes of compounds that bind directly to LPS and thereby neutralize its effects are being examined. These consist of anti-LPS monoclonal antibodies (mAbs), naturally occurring proteins and their derivatives (e.g., bactericidal/permeability-increasing protein [BPI], Limulus anti-LPS factor [LALF]), and certain antibiotics (polymyxin B, taurolidine). The molecular biology of BPI, LALF, and LPS binding protein (LBP, which augments the host response to LPS) is of considerable interest, as each demonstrates considerable genetic sequence homology. Although two anti-LPS monoclonal antibodies (HA-1A, E5) did not demonstrate efficacy during sepsis syndrome, information obtained from these clinical trials provided investigators with the ability to better understand this disease process. However, a detailed understanding of the biology of endotoxin antagonism is beginning to emerge, and the application of this knowledge in the clinical setting provides hope that it may be possible to reduce the mortality of sepsis syndrome caused by these microorganisms to a statistic well below the current 40%.

β2-Microglobulin knockout mice treated with anti-asialoGM1 exhibit improved hemodynamics and cardiac contractile function during acute intra-abdominal sepsis

“…Proinflammatory cytokines are known to directly contribute to sepsis-induced myocardial depression and other alterations in hemodynamic function observed in septic patients as well as in experimental models of sepsis (9,17,23,25). Most prior studies have focused on macrophages and monocytes as the primary cell types driving the proinflammatory response during sepsis (8,10,21). In our prior report, we showed that depletion of NK and CD8 ϩ T cells significantly contributes to the resistance of ␤2M/␣AsGM1 mice to CLP-induced mortality.…”

Cytokine Responses to CpG DNA in Human Leukocytes

“…Lipopolysaccharide from the cell wall of Gram‐negative bacteria has for a long time been known as a very potent endotoxin [2] and is recognized by the immune cells through the TLR4. Peptidoglycan is a bacterial cell wall component found in both Gram‐positive and Gram‐negative bacteria.…”

“…Sepsis occurs as a dysregulated inflammatory response to infection that can cause multiple‐organ dysfunction syndrome (MODS), circulatory failure and eventually death [1]. Among the bacterial components contributing to the development of sepsis, Gram‐negative bacterial lipopolysaccharide (LPS) has been thought to be the triggering molecule of the excessive inflammatory response [2]. When bacteria are allowed to enter into the blood stream and mammalian tissue during an infection, endotoxins such as LPS are recognized by macrophages by virtue of Toll‐like receptors (TLRs).…”

Effect of Resveratrol on NF-κB Activity in Rat Peritoneal Macrophages

“…Cytokines (TNF-α and IL-1) secreted by macrophages were centrally involved in the inflammatory responses. Suppressing the activation of macrophages could reduce the production of cytokines and subsequently relieve systemic or local inflammatory injury (Dunn, 2000;Kherani et al, 2004;Leiro et al, 2002;Park et al, 2004). Bertelli et al (2001) demonstrated that RESV could modulate the production of vascular cell adhesion molecule-1 (VCAM-1) in TNF-α stimulated endothelial cells and inhibit the increase of vascular permeability induced by TNF-α.…”