Omega-3 vs. omega-6 lipid emulsions exert differential influence on neutrophils in septic shock patients: impact on plasma fatty acids and lipid mediator generation

Abstract

Objective: To compare the effects of a conventional omega-6 lipid infusion and a fish oil based (omega-3) lipid infusion for parenteral nutrition on neutrophil function, lipid mediators, and plasma free fatty acids.

Design and setting: Open-label, randomized, pilot study in a university hospital medical intensive care unit and experimental laboratory.

Patients and participants: Ten patients with septic shock and eight healthy controls.

Interventions: Patients (five per group) requiring parenteral nutrition received intravenously either a omega-3 or a omega-6 lipid emulsion for a 10-day period.

Measurements and results: At baseline levels of plasma free fatty acids were elevated several-fold, including high concentrations of the omega-6 lipid precursor arachidonic acid (AA). Neutrophils isolated from septic patients displayed markedly reduced responsiveness to ex vivo stimulation, including lipid mediator generation [leukotrienes (LT), PAF], respiratory burst, and phosphoinositide hydrolysis signaling. Under the omega-6 lipid infusion regimen abnormalities in plasma free fatty acids and impairment of neutrophil functions persisted or worsened. In contrast, a rapid switch in the plasma free fatty acid fraction to predominance of the omega-3 acids eicosapentaenoic acid and docosahexaenoic acid over AA occurred in response to omega-3 lipid infusion. LTB(5), in addition to LTB(4), appeared upon neutrophil stimulation originating from these patients, and neutrophil function was significantly improved in the omega-3 lipid group.

Conclusions: omega-3 vs. omega-6 lipid emulsions differentially influence the plasma free fatty acid profile with impact on neutrophil functions. Lipid-based parenteral nutrition in septic patients may thus exert profound influence on sequelae and status of immunocompetence and inflammation.

Fig. 1.

Generation of leukotriene (LT) B₄ (a), LTB₅ (b), synthesis of platelet-activating factor (PAF, c), and respiratory burst (d). PMN were isolated on days 1, 3, 7, and 10 of the lipid infusion regimen and subsequently stimulated with A23 187 (LTs and PAF) or fMLP (respiratory burst) as described. Generation of LTB₄ and PAF in PMN of septic patients was markedly lower than in healthy controls (*p<0.05). LTB₄ release did not differ significantly between the treatment groups. LTB₅ generation was detected only in the ω-3 lipid infusion group (note different scales for LTB₄ and LTB₅). On day 7 PAF generation and respiratory burst in the ω-3 lipid infusion group were significantly higher than in the ω-6 lipid infusion group (^§ p<0.05, mean ±SEM are given)

Fig. 2.

Neutrophil inositol phosphate generation. Neutrophil inositol phosphate (IP) generation evoked by fMLP. IP₃, IP₂, and IP₁ are summarized as IP_x. Mean ±SEM is given. The IP_x generation of the ω-3 lipid infusion group on day 7 differed significantly from that in the ω-6 lipid infusion group at this time (*p<0.05) and was significantly increased over baseline (day 1). The control group was significantly higher than all other groups (^§ p<0.05)

Fig. 3.

Platelet thromboxane (Tx) generation in response to thrombin. TxA₂/TxA₃ generation of isolated platelets was measured by post-HPLC enzyme-linked immunosorbent assay as described. Mean ±SEM of the TxA₃/TxA₂ ratio is given for the different groups