Pulmonary pathophysiological changes in sheep caused by endotoxin precursor, lipid X.
The chemical structure of the biologically active lipid A portion of Gram-negative endotoxin [lipopolysaccharide (LPS)] has recently been elucidated. This was greatly facilitated by the isolation of an Escherichia coli mutant that accumulates large quantities of lipid X, a novel monosaccharide precursor of lipid A (C. R. H. Raetz, Rev. Infect. Dis. 6: 463-471, 1984). We now report on the activity of lipid X in the lung-lymph model in sheep. We have measured the response to cumulative bolus injections of lipid X (2,3-diacylglucosamine 1-phosphate) in six chronically instrumented unanesthetized sheep. Lipid X at a total dose of 40 micrograms/kg produced a biphasic pattern of changes. The early phase was characterized by a rapid transient pulmonary arterial constrictive response that was dose dependent, accompanied by a delayed transient increase in lung-lymph flow (P less than 0.05), a significant (P less than 0.01) decrease in arterial blood O2 tension and an increase (P less than 0.05) in lung-lymph protein clearance. Protein permeability changes in the first phase are not usually seen following endotoxin injection. However, like endotoxin, lipid X also produced a late phase (3-6 h later) of increased lung vascular permeability to fluid and protein as reflected by significant (P less than 0.05) increases in both lung-lymph flow and lung-lymph protein clearance in the presence of stable pulmonary vascular pressures at or below base-line levels. We conclude that some of the pulmonary pressor activity of the endotoxin molecule can be attributed to the lipid X substructure. Furthermore, changes in vascular permeability may also be initiated by this substance.
D000818:Animals; D001784:Blood Gas Analysis; D055598:Chemical Phenomena; D002621:Chemistry; D006017:Glycolipids / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D008208:Lymphatic System / Q000187:drug effects; D008433:Mathematics; D012756:Sheep
D006017:Glycolipids; D008070:Lipopolysaccharides; C044283:lipid X