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December 1995

Liposomes Modulate Kupffer Cell Endotoxin Response

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).

Arch Surg. 1995;130(12):1266-1272. doi:10.1001/archsurg.1995.01430120020003

Objectives:  To test the hypothesis that pretreatment with liposomes enriched with the ω3 fatty acid docosahexaenoic acid (22:6ω3) 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 ω3, and docosahexaenoic acid 22:6ω3 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 χ2 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)