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Paul Bankey, MD, PhD; Ernest Beecherl, MD; Doug Bibus, MS; Dana See; Kendra McIntyre

Arch Surg. 1995;130(12):1266-1272.

Abstract
Objectives
To test the hypothesis that pretreatment with liposomes enriched with the 3 fatty acid docosahexaenoic acid (22:63) will alter the Kupffer's cell and systemic cytokine (tumor necrosis factor and interleukin-6) response to endotoxin challenge, and to demonstrate alterations in Kupffer's cell phospholipid fatty acid composition after in vivo liposome treatment.

Design
Nonrandomized controlled laboratory investigation in Wistar rats.

Interventions
Animals were assigned to three pretreatment groups: no liposomes; liposomes, 100 mg/kg; or liposomes, 400 mg/kg given by bolus intravenous injection with the animals under inhalation anesthesia. Eighteen hours after liposome treatment, each group was challenged with Escherichia coli lipopolysaccharide (3 mg/kg intraperitoneally in 10 mL of lactated Ringer's solution) or lactated Ringer's solution only. In a separate set of experiments, Kupffer's cells were obtained from animals pretreated with liposome, 400 mg/kg, or controls and challenged with lipopolysaccharide (1, 100, or 10⁴ ng/mL) in vitro.

Outcome Measures
Serum and Kupffer's cell supernatant tumor necrosis factor and interleukin-6 bioactivity, Kupffer's cell phospholipid fatty acid composition, survival, and liver histologic findings.

Results
In vivo liposome pretreatment (400 mg/kg) resulted in significant increases in serum tumor necrosis factor and interleukin-6 levels 90 minutes after intraperitoneal lipopolysaccharide challenge (P<.05 vs no liposomes). Kupffer's cells isolated from liposome-treated animals (400 mg/kg) compared with untreated controls release significantly more tumor necrosis factor and interleukin-6 after lipopolysaccharide stimulation in vitro in a dose-dependent response (P<.05). Liposome treatment increased total polyunsaturated fatty acid, total 3, and docosahexaenoic acid 22:63 content in Kupffer's cell phospholipids compared with untreated controls. Survival 24 hours after lipopolysaccharide challenge was reduced by liposome (400 mg/kg) pretreatment (P<.05 by ² test). Livers from each treatment group demonstrated focal areas of hepatocyte necrosis and inflammatory cells.

Conclusion
Liposome pretreatment increases the circulating and Kupffer's cell cytokine response to endotoxemia, increases Kupffer's cell polyunsaturated fatty acid content, and is associated with reduced survival.

(Arch Surg. 1995;130:1266-1272)

Author Affiliations
From the Department of Surgery, The University of Texas Southwestern Medical Center at Dallas (Drs Bankey and Beecherl and Mss See and McIntyre); and Hormel Institute, Austin, Minn (Mr Bibus).

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