Bacterial endotoxins and pathogenesis of Gram-negative infections: current status and future direction

Abstract

100 years after the discovery of a bacterial 'endotoxin', 50 years after the introduction of antibiotics and 25 years after the routine use of intensive care units to support septic shock patients, Gram-negative infections continue to account for significant morbidity and mortality. In the coming decade, basic research on the structure/function of LPS, the cytokine cascade, and receptor-mediated intracellular signalling responses to LPS and cytokines will provide a greater understanding of the molecular, cellular and systemic responses to endotoxin and infection. New therapeutic agents now emerging from research, and better designed clinical trials to assess those agents will contribute to the next significant decline in sepsis- and shock-related morbidity and mortality. This article summarizes the findings of a workshop convened at the National Institutes of Health (NIH) to examine current research on endotoxin and Gram-negative septic shock.

Organism-specific platelet response and factors affecting survival in thrombocytopenic very low birth weight babies with sepsis

“…34,35 Platelet Toll-like receptor 4 expression also mediates lipopolysaccharide-mediated thrombocytopenia and the release of tumor necrosis factor-a by causing platelet sequestration in the lungs in the presence of neutrophils. 36 As endotoxemia is often accompanied by a microvascular inflammatory response, 37,38 cytokines and bacterial lipopolysaccharide probably trigger this response through the activation of platelets, leukocytes or both. This microvascular inflammatory response could be responsible for the multiorgan failure that occurs with sepsis in preterm babies.…”

Cathelicidin Family of Antibacterial Peptides CAP18 and CAP11 Inhibit the Expression of TNF-α by Blocking the Binding of LPS to CD14+ Cells

“…LPS, also known as endotoxin, is the outer membrane component of Gram-negative bacteria, which has an extremely biologically activity and a key role in the pathogenesis of endotoxin shock associated with the septic syndrome (1,32). LPS activates mononuclear phagocytes (monocytes and macrophages) and other types of cells to produce and release potent inflammatory mediators, of which TNF-␣ appears to be very important for the development of endotoxin shock (2-4).…”

“…Synthetic lipid A LA-15-PP (506) was obtained from Daiichi Pure Chemicals (Tokyo, Japan). A 37-mer peptide of human CAP18 (L 1 LGDFFRKSKE KIGKEFKRIVQRIKDFLRMLVPRTES 37 ), a guinea pig CAP11 peptide with a free sulfhydryl group of cysteine residue (G 1 LRKKFRKTRKR IQKLGRKIGKTGRKVWKAWREYGQIPYPCRI 43 ), and a 20-mer peptide of p40-phox, an NADPH oxidase component (L 1 HITQQDNYSVY NTTPSATQ 20 ) (24) were synthesized by the solid phase method on a peptide synthesizer (model PSSM-8; Shimadzu, Kyoto, Japan) by F-moc chemistry. The peptides were eluted from the resin using a standard protocol and purified to homogeneity by reversed phase HPLC on a Cosmosil 5C 18 column (Nacalai Tesqu, Kyoto, Japan), using a 0 -70% acetonitrile gradient in 0.1% trifluoroacetic acid.…”

“…We have isolated two members of cathelicidins, CAP18 (cationic antibacterial proteins of 18 kDa) and CAP11 (cationic antibacterial polypeptide of 11 kDa) from rabbit and human neutrophils (18,19), and guinea pig neutrophils (20,21), respectively. CAP18 is a precursor form of cathelicidins, and its carboxyl-terminal antibacterial peptide comprising 37 aa residues (L 1 LGDFFRKSKEKIGKEFKRIVQRIKDFLRN LVPRTES 37 ) has been recently identified in humans (13). In contrast, CAP11 is a carboxyl-terminal antibacterial peptide cleaved from its precursor and is a homodimer of G 1 LRKKFRKTR KRIQKLGRKIGKTGRKVWKAWREYGQIPYPCRI 43 ) joined with one disulfide bond (20,21).…”

“…LPS activates mononuclear phagocytes (monocytes and macrophages) and other types of cells to secrete TNF-␣, IL-1␤, IL-6, and other cytokines, which mediate the development of septic shock (1). In certain animal models TNF-␣ is principal for the lethality induced by LPS (2)(3)(4).…”