LIPOSOMES MODULATE KUPFFER CELL ENDOTOXIN RESPONSE

Objectives: To test the hypothesis that pretreatment with liposomes en riched with the omega 3 fatty acid docosahexaenoic acid (22:6 omega 3) will alter the Kupffer's cell and systemic cytokine (tumor necrosis f actor and interleukin-6) response to endotoxin challenge, and to demon strate alterations in Kupffer's cell phospholipid fatty acid compositi on after in vivo liposome treatment. Design: Nonrandomized controlled laboratory investigation in Wistar rats. Interventions: Animals were a ssigned 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 lipopolysa ccharide (3 mg/kg intraperitoneally in 10 mL of lactated Ringer's solu tion) or lactated Ringer's solution only. In a separate set of experim ents, Kupffer's cells were obtained from animals pretreated with lipos ome, 400 mg/kg, or controls and challenged with lipopolysaccharide (1, 100, or 10(4) ng/mL) in vitro. Measures: Serum and Kupffer's cell sup ernatant tumor necrosis factor and interleukin-6 bioactivity, Kupffer' s cell phospholipid fatty acid composition, survival, and liver histol ogic findings. Results: In vivo liposome pretreatment (400 mg/kg) resu lted in significant increases in serum tumor necrosis factor and inter leukin-6 levels 90 minutes after intraperitoneal lipopolysaccharide ch allenge (P < .05 vs no liposomes). Kupffer's cells isolated from lipos ome-treated animals (400 mg/kg) compared with untreated controls relea se significantly more tumor necrosis factor and interleukin-6 after li popolysaccharide stimulation in vitro in a dose-dependent response (P < .05), Liposome treatment increased total polyunsaturated fatty acid, total omega 3, and docosahexaenoic acid 22:6 omega 3 content in Kupff er's cell phospholipids compared with untreated controls. Survival 24 hours after lipopolysaccharide challenge was reduced by liposome (400 mg/kg) pretreatment (P < .05 by chi(2) test). Livers from each treatme nt group demonstrated focal areas of hepatocyte necrosis and inflammat ory cells. Conclusion: Liposome pretreatment increases the circulating and Kupffer's cell cytokine response to endotoxemia, increases Kupffe r's cell polyunsaturated fatty acid content, and is associated with re duced survival.