Novel therapies for sepsis: antiendotoxin therapies

Abstract

Severe sepsis and septic shock is a common problem encountered in the critical care unit with an estimated incidence in the US of 750,000 cases/year and a mortality rate of 30-50%. Sepsis involves a complex interaction between bacterial factors and the host immune system producing a systemic inflammatory state that may progress to multiple organ failure and death. Endotoxin (a lipopolysaccharide) released from Gram-negative bacteria has been implicated as a potent, prototypical stimulus of the immune response to bacterial infection. Current antiendotoxin strategies utilise various approaches ranging from the prevention of binding to endotoxin receptors with antibodies (monoclonal or polyclonal) against endotoxin or endotoxin receptor/carrier molecules (antiCD14 or antilipopolysaccharide-binding protein antibodies), enhancing clearance or neutralisation (haemoperfusion, lipoproteins, lipopolysaccharide-neutralising proteins) or impairing cellular signalling (lipid A analogues, tyrosine kinase inhibitors). In the future, innovative therapies involving Toll-like receptors and their downstream signalling elements will be developed. This review discusses current knowledge regarding endotoxin signalling, antiendotoxin therapies currently under development, and future areas for research.

Interaction of Antimicrobial Peptide Temporin L with Lipopolysaccharide In Vitro and in Experimental Rat Models of Septic Shock Caused by Gram-Negative Bacteria

“…Alternative pharmaceutical therapies targeting single proinflammatory mediators and/or endotoxin are in development, but despite good results in animal models, their effects in humans-as proven by a number of clinical trials-have been so far disappointing (18). Three main such anti-inflammatory strategies aimed at improving the outcome of septic shock have been investigated, based on the administration of glucocorticoids, the development of endotoxin-directed monoclonal antibodies and other agents capable of binding and neutralizing LPS, or the inhibition of proinflammatory cytokines (e.g., anti-TNF antibodies, interleukin-1 receptor antagonists) (35,47,55). Another therapeutic approach with interesting prospects is offered by extracorporeal blood purification, achieved through several distinct techniques (37,50).…”

Endotoxin (Lipopolysaccharide) Neutralization by Innate Immunity Host-Defense Peptides

“…The first one utilized LPS receptor antagonists including anti-CD14 antibodies, anti-LBP antibodies, and lipid A analogs, all of which bind to essential components participating in the signaling mechanism (17,18). The second approach utilized LPS blockers such as anti-lipid A antibodies and modified liposomes, both of which bind to LPS itself and prevent its ability to activate the macrophages (19,20). Note, however, that although these studies have helped us to understand the steps involved in LPS neutralization, the approaches used could not deal with the bacteria from which the LPS is derived (19).…”

UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglucosamine Deacetylase Functions through a General Acid-Base Catalyst Pair Mechanism

“…Lipid A is also known as endotoxin and is the immunomodulatory portion of LPS that triggers the immune system in septic shock. As a consequence, inhibition of lipid A biosynthesis is proposed as a strategy for both the development of novel antibiotics and anti-endotoxins in the treatment of septic shock (1)(2)(3)(4)(5).…”