Triglyceride-rich lipoproteins prevent septic death in rats.
Triglyceride-rich lipoproteins bind and inactive bacterial endotoxin in vitro and prevent death when given before a lethal dose of endotoxin in animals. However, lipoproteins have not yet been demonstrated to improve survival in polymicrobial gram-negative sepsis. We therefore tested the ability of triglyceride-rich lipoproteins to prevent death after cecal ligation and puncture (CLP) in rats. Animals were given bolus infusions of either chylomicrons (1 g triglyceride/kg per 4 h) or an equal volume of saline for 28 h after CLP. Chylomicron infusions significantly improved survival (measured at 96 h) compared with saline controls (80 vs 27%, P < or = 0.03). Chylomicron infusions also reduced serum levels of endotoxin, measured 90 min (26 +/- 3 vs 136 +/- 51 pg/ml, mean +/- SEM, P < or = 0.03) and 6 h (121 +/- 54 vs 1,026 +/- 459 pg/ml, P < or = 0.05) after CLP. The reduction in serum endotoxin correlated with a reduction in serum tumor necrosis factor, measured 6 h after CLP (0 +/- 0 vs 58 +/- 24 pg/ml, P < or = 0.03), suggesting that chylomicrons improve survival in this model by limiting macrophage exposure to endotoxin and thereby reducing secretion of inflammatory cytokines. Infusions of a synthetic triglyceride-rich lipid emulsion (Intralipid; KabiVitrum, Inc., Alameda, CA) (1 g triglyceride/kg) also significantly improved survival compared with saline controls (71 vs 27%, P < or = 0.03). These data demonstrate that triglyceride-rich lipoproteins can protect animals from lethal polymicrobial gram-negative sepsis.
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Department of Surgery, University of California, San Francisco 94143, USA.
Grunfeld
C
C
Kumwenda
Z L
ZL
Calhoun
M C
MC
Kane
J P
JP
Feingold
K R
KR
Rapp
J H
JH
D000818:Animals; D002432:Cecum; D002914:Chylomicrons / Q000737:chemistry / Q000627:therapeutic use*; D004731:Endotoxins / Q000097:blood; D005217:Fat Emulsions, Intravenous / Q000627:therapeutic use*; D007416:Intestinal Perforation / Q000150:complications; D008026:Ligation; D008074:Lipoproteins / Q000737:chemistry / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000209:etiology; D014280:Triglycerides / Q000032:analysis*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D002914:Chylomicrons; D004731:Endotoxins; D005217:Fat Emulsions, Intravenous; D008074:Lipoproteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha