Lipid X ameliorates pulmonary hypertension and protects sheep from death due to endotoxin.
Lipid X (2,3-diacylglucosamine-1-phosphate) is a novel monosaccharide precursor of lipid A that has some of the physiologic activities of endotoxin but little toxicity. To determine whether lipid X would interfere with the toxic effects of endotoxin, we pretreated sheep with either 100 or 200 micrograms of lipid X per kg of body weight and then challenged them with a potentially fatal dose of Escherichia coli endotoxin (20 micrograms/kg). Twenty-one sheep underwent pulmonary artery catheterization and were monitored for changes in pulmonary artery pressure, temperature, pH, partial O2 pressure, partial CO2 pressure, blood pressure, and cell counts over 7 h. Overall mortality for control animals was 37% versus 5.3% for pretreated animals. None of the 13 animals pretreated with 100 micrograms of lipid X per kg died. These differences in survival were significant (P less than 0.05). Animals pretreated with 100 micrograms of lipid X per kg had significantly lower pulmonary artery pressure during both phases 1 and 2 of endotoxin-induced pulmonary artery hypertension. A higher dose of lipid X, 200 micrograms/kg, produced pulmonary hypertension. Perhaps because lipid X is a subunit of lipid A, lipid X shows a partial pyrogenic effect while also decreasing the pyrogenic activity of complete lipopolysaccharide (LPS). Lipid X did not prevent endotoxin-induced neutropenia or moderate hypotension in response to LPS. Lipid X is a potential prototype compound for a new type of chemotherapy directed at blocking the harmful effects of LPS during bacterial septicemia.
Golenbock
D T
DT
Department of Medicine, University of Wisconsin, Madison 53706.
Will
J A
JA
Raetz
C R
CR
Proctor
R A
RA
D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D005260:Female; D006017:Glycolipids / Q000627:therapeutic use*; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D007958:Leukocyte Count; D008050:Lipid A / Q000378:metabolism; D008297:Male; D012756:Sheep
D004731:Endotoxins; D006017:Glycolipids; D008050:Lipid A; C044283:lipid X