Targeting Bacterial Endotoxin

Abstract

The term sepsis describes a potentially lethal clinical condition that develops as a result of a dysregulated host response to bacterial infection. The most common bacterial component implicated in initiating the septic syndrome is a cell wall molecule derived from Gram-negative bacteria, known as lipopolysaccharide (LPS) or endotoxin. Like all mammals, humans are equipped with an LPS-sensing machinery consisting, primarily, of LPS-binding protein (LBP), CD14, a glycosylphosphatidylinositol (GPI)-anchored monocyte differentiation antigen, and toll-like receptor 4 (TLR4), a signal-transducing integral membrane protein. Modest stimulation of TLR4 facilitates the elimination of invading microorganisms. Potent TLR4 stimulation, however, produces severe reactions in the host, often leading to multiple organ failure and death. The search for pharmaceuticals that reduce mortality in septic patients has been a painstaking process. Thus far, only a few compounds have been found to significantly reduce mortality rates. Perhaps one of the more promising therapeutic strategies currently pursued is based on the identification of synthetic or naturally occurring substances that neutralize LPS or inhibit LPS-mediated activation of host immune cells, such as monocytes and macrophages. Here, we describe a number of diverse molecular structures with a capacity to either enhance or blunt LPS-induced monocyte activation. The underlying molecular mechanisms are discussed.

The Novel Lipopolysaccharide-Binding Protein CRISPLD2 Is a Critical Serum Protein to Regulate Endotoxin Function

“…S7). 5 For measuring anti-LPS Ab in mouse serum, LPS (100 ng/ml) in sodium carbonate buffer (pH 9.5) was plated in 96-well microtiter plates overnight, followed by treatment with 10% FCS in PBS for 60 min. Mouse sera in 1-to 100-fold dilutions in PBS were added to the immobilized LPS, and HRPconjugated donkey anti-mouse Ab (Jackson ImmunoResearch Laboratories) was used to react with plate-bound anti-LPS Abs.…”

“…Decades ago immunologists identified, in the cell wall of Gram-negative bacteria, a highly bioactive LPS composed of a monomorphic lipid core and a polymorphic polysaccharide coat that stimulates immune functions in a systemic rather than local fashion (3). LPS-producing Gram-negative bacteria pose a threat to the health of mammals and may kill them by septic shock (4,5).…”

The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice

“…The infectious components (including bacterial cell walls) function as foreign ligands of toll-like receptors, and systemic inflammation elicits thrombosis and eventually multiple organ failure (4,26). Furthermore, albuminuria is also a common event during septic diseases (6,25,28), along with inflammatory responses.…”

Endocannabinoids mediate hyposalivation induced by inflammogens in the submandibular glands and hypothalamus

“…37 It was shown that LPS infused intraductally into the rat SMG proved to be a very effective inflammogen, since there was a rapid increase in gland weight at 3 h. 38 The majority of salivary gland pathologies are inflammatory and most salivary gland inflammatory diseases have in common an associated salivary hypofunction. 39, 40 The present results showed that the acute inflammatory state induced by direct administration of LPS into the SMG decreased MC-induced salivary secretion by activating the endocannabinoid system, since it was completely blocked by the administration of the selective CB1 receptor antagonist AM251 through the same route.…”