Novel therapies for sepsis: antiendotoxin therapies.
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.
Manocha
Sanjay
S
Section of Critical Care Medicine, Health Sciences Center, University of Manitoba, 820 Sherbrook Street, Winnipeg, Manitoba, Canada, R3A 1R.
Feinstein
Daniel
D
Kumar
Aseem
A
Kumar
Anand
A
D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D004731:Endotoxins / Q000037:antagonists & inhibitors*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000187:drug effects; D008562:Membrane Glycoproteins; D011112:Polymyxin B / Q000627:therapeutic use; D018805:Sepsis / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D013654:Taurine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013829:Thiadiazines / Q000627:therapeutic use; D014611:Vaccination; D000099231:Lipopolysaccharide-Binding Protein
D000209:Acute-Phase Proteins; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D011112:Polymyxin B; D013654:Taurine; D013829:Thiadiazines; D000099231:Lipopolysaccharide-Binding Protein; C012566:taurolidine