A reconstituted, apolipoprotein A-I containing lipoprotein reduces tumor necrosis factor release and attenuates shock in endotoxemic rabbits.
A reconstituted lipoprotein, containing human apolipoprotein A-I and phosphatidylcholine (1:200, molar ratio), referred to as ApoLipo, was used prophylactically in an endotoxin shock model in anesthetized rabbits. ApoLipo was administered at a dose of 75 mg protein/kg body weight 15 min before the beginning of a slow, continuous lipopolysaccharide (LPS, endotoxin) infusion (4.17 micrograms LPS/kg/hr). During the 6 hr LPS infusion, the Control-LPS group manifested a marked increase in serum tumor necrosis factor (TNF, peak value 7.82 [2.7-11.2] ng/ml at 1 hr), and many of the pathophysiologic sequelae of endotoxin shock, including hypotension (MAP: 59 +/- 7 mmHg) and metabolic acidosis (BE: -9.9 +/- 2.7) at 3 hr, and a severe neutropenia developed rapidly (PMN count: 5 +/- 3% of baseline at 30 min). In the ApoLipo treated group, serum TNF levels did not rise during the course of LPS infusion (0.1 [0.06-0.64] ng/ml at 1 hr). Hypotension (77 +/- 2 mmHg) and acidosis (-2.7 +/- 0.4) were also significantly attenuated, and the appearance of leukopenia was delayed by 1 hr (110 +/- 12% at 30 min, but 9 +/- 2% at 2 hr). Endotoxemia in the ApoLipo treated group was reduced in comparison to controls, albeit nonsignificantly. The infusion of the same dose of phosphatidylcholine without apoA-I was significantly less efficacious.
Hubsch
A P
AP
Central Laboratory, Swiss Red Cross, Bern.
Powell
F S
FS
Lerch
P G
PG
Doran
J E
JE
D000138:Acidosis / Q000517:prevention & control; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D004195:Disease Models, Animal; D004731:Endotoxins; D007022:Hypotension / Q000517:prevention & control; D007970:Leukopenia / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D010713:Phosphatidylcholines; D010976:Platelet Count; D011817:Rabbits; D012772:Shock, Septic / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016632:Apolipoprotein A-I; D004731:Endotoxins; D010713:Phosphatidylcholines; D014409:Tumor Necrosis Factor-alpha