Immunomodulation by lipid emulsions in pulmonary inflammation: a randomized controlled trial.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care units. As there is rising evidence about immuno-modulatory effects of lipid emulsions required for parenteral nutrition of ARDS patients, we sought to investigate whether infusion of conventional soybean oil (SO)-based or fish oil (FO)-based lipid emulsions rich in either n-6 or n-3 fatty acids, respectively, may influence subsequent pulmonary inflammation. METHODS: In a randomized controlled, single-blinded pilot study, forty-two volunteers received SO, FO, or normal saline for two days. Thereafter, volunteers inhaled pre-defined doses of lipopolysaccharide (LPS) followed by bronchoalveolar lavage (BAL) 8 or 24 h later. In the murine model of LPS-induced lung injury a possible involvement of resolvin E1 (RvE1) receptor ChemR23 was investigated. Wild-type and ChemR23 knockout mice were infused with both lipid emulsions and challenged with LPS intratracheally. RESULTS: In volunteers receiving lipid emulsions, the fatty acid profile in the plasma and in isolated neutrophils and monocytes was significantly changed. Adhesion of isolated monocytes to endothelial cells was enhanced after infusion of SO and reduced by FO, however, no difference of infusion on an array of surface adhesion molecules was detected. In neutrophils and monocytes, LPS-elicited generation of pro-inflammatory cytokines increased in the SO and decreased in the FO group. LPS inhalation in volunteers evoked an increase in neutrophils in BAL fluids, which decreased faster in the FO group. While TNF-α in the BAL was increased in the SO group, IL-8 decreased faster in the FO group. In the murine model of lung injury, effects of FO similar to the volunteer group observed in wild-type mice were abrogated in ChemR23 knockout mice. CONCLUSIONS: After infusion of conventional lipid emulsions, leukocytes exhibited increased adhesive and pro-inflammatory features. In contrast, FO-based lipid emulsions reduced monocyte adhesion, decreased pro-inflammatory cytokines, and neutrophil recruitment into the alveolar space possibly mediated by ChemR23-signaling. Lipid emulsions thus exert differential effects in human volunteers and mice in vivo. TRIAL REGISTRATION: DRKS00006131 at the German Clinical Trial Registry, 2014/05/14.

Effects of short-term infusion of lipid emulsions on pro-inflammatory cytokines and lymphocyte apoptosis in septic and non-septic rats.

Long-term administration of PUFA is known to modulate immune functions and apoptotic pathways depending on the respective amount of n-6 and n-3 fatty acids (FA). Data on short-term effects on apoptotic pathways are rare. Apoptosis of splenic lymphocytes is the hallmark of detrimental sepsis. Therefore, we aimed to compare the immediate effects of parenterally administered n-6-enriched soyabean oil (SO)- and n-3-enriched fish oil (FO)-based lipid emulsions after laparotomy (LAP; sham procedure) and after induction of acute, severe sepsis by caecal ligation and incision. After 390 min of observation time, plasma was analysed for IL-1ß, IL-6 and NEFA. Apoptosis in splenic lymphocytes was quantified by Annexin-V expression. After LAP, infusion of both FO and SO did not change cytokine concentrations. Sepsis increased both cytokines. FO but not SO further augmented the rise. After LAP, SO increased NEFA, and both lipid emulsions reduced free arachidonic acid (AA). Sepsis resulted in a dramatic decrease in NEFA and AA. The drop in NEFA and AA was prevented by both SO and FO. In addition, FO resulted in an increased concentration of n-3 FA under both conditions. Infusion of both lipid emulsions induced apoptosis in splenic lymphocytes after LAP. Sepsis-induced apoptosis was not further enhanced by FO or SO. The present study shows that short-term administration of FO as opposed to SO caused pro-inflammatory effects during sepsis. Moreover, short-term administration of both SO and FO suffices to induce apoptosis in splenic lymphocytes. Finally, SO and FO do not further enhance sepsis-induced splenic apoptosis.

Induction of lymphocyte apoptosis in a murine model of acute lung injury--modulation by lipid emulsions.

Acute lung injury (ALI) and sepsis are the major causes of mortality in intensive care units. Lymphocytes apoptosis is a hallmark feature of late detrimental sepsis. Parenteral nutrition in critically ill patients is based on lipid emulsions, but the impact of ALI and lipid emulsions on lymphocytes has not been defined. The effects of intravenously infused conventional soybean oil (SO)-based and new olive oil (OO)-based emulsions on splenic and blood lymphocytes were investigated in a murine model of endotoxin-induced ALI. After LPS challenge and infusion of lipid emulsions, apoptosis of lymphocytes and lung injury were assessed by flow cytometry, Western blot, and histology. Induction of ALI led to a time-dependent decline in splenic and circulating lymphocyte numbers and an increase in apoptosis, with engagement of the extrinsic apoptotic pathway. Both SO- and OO-based emulsions promoted the apoptosis of splenic lymphocytes before induction of ALI. The OO-based emulsions exhibited lower proapoptotic activity than did SO-based emulsions, an observation paralleled by the induction of survival factors. Induction of ALI increased the mortality of mice receiving SO-based emulsions compared with OO-based emulsions and normal saline. Splenic lymphocyte apoptosis is apparent in murine ALI, which may be linked to detrimental outcome. Infusion of lipid emulsions per se provoked splenic lymphocyte apoptosis. Infusion of SO-based emulsions further augmented the apoptosis of splenic and circulating lymphocytes in ALI and led to increased mortality in mice. These findings may be of relevance for patients experiencing ALI that require parenteral nutrition.

Immunomodulation by n-3- versus n-6-rich lipid emulsions in murine acute lung injury--role of platelet-activating factor receptor.

OBJECTIVE: Cytokines, platelet-activating factor (PAF), and eicosanoids control local and systemic inflammation. Conventional soybean oil-based lipid emulsions used for parenteral nutrition may aggravate the leukocyte inflammatory response or adhesion to the vessel wall. Fish oil-based lipid emulsions, in contrast, may exert an anti-inflammatory effect. DESIGN: We investigated the impact of lipid emulsions on leukocyte invasion, protein leakage, and cytokines in two murine models of acute inflammation. SETTING: Research laboratory of a university hospital. SUBJECTS: Wild-type mice and PAF-receptor knockout mice. INTERVENTIONS: Mice received an infusion of normal saline, fish oil- or soybean oil-based lipid emulsions before lipopolysaccharide challenge. MEASUREMENTS AND MAIN RESULTS: Preinfusion with soybean oil resulted in increased leukocyte invasion, myeloperoxidase activity, and protein leakage and exaggerated release of tumor necrosis factor (TNF)-alpha as well as macrophage inflammatory protein (MIP)-2 into the alveolar space after intratracheal lipopolysaccharide challenge. In contrast, preinfusion with fish oil reduced leukocyte invasion, myeloperoxidase activity, protein leakage, and TNF-alpha as well as MIP-2 generation. Corresponding profiles were found in plasma following intraperitoneal lipopolysaccharide application: Soybean oil increased but fish oil decreased the TNF-alpha and MIP-2 formation. When PAF-receptor-deficient mice were challenged with lipopolysaccharide, leukocyte invasion, lung tissue myeloperoxidase, cytokine generation, and alveolar protein leakage corresponded to those observed in wild-type animals. Fish oil and soybean oil lost their diverging effects on leukocyte transmigration, myeloperoxidase activity, leakage response, and cytokine generation in these knockout mice. Similarly, the differential impact of both lipid emulsions on these lipopolysaccharide-provoked changes was suppressed after pretreating animals with a PAF-receptor antagonist. CONCLUSIONS: Fish oil- vs. soybean oil-based lipid infusions exert anti- vs. proinflammatory effects in murine models of acute inflammation. The PAF/PAF-receptor-linked signaling appears to be a prerequisite for this differential profile.