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Byline: Konstantin Mayer (1), Christine Fegbeutel (1), Katja Hattar (1), Ulf Sibelius (1), Hans-Joachim Kramer (1), Kai-Uwe Heuer (1), Bettina Temmesfeld-Wollbruck (1), Stephanie Gokorsch (1), Friedrich Grimminger (1), Werner Seeger (1) Keywords: Septic shock; Neutrophils; Leukotrienes; Fish oils; Thromboxanes; Total parenteral nutrition 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.sub.5, in addition to LTB.sub.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. Author Affiliation: (1) Department of Internal Medicine, Justus Liebig University, Klinikstrasse 36, Giessen, Germany Article History: Received Date: 14/05/2002 Accepted Date: 03/06/2003 Online Date: 25/07/2003 Article note: This work was supported by the Deutsche Forschungsgemeinschaft (SFB 547 'Kardiopulmonales Gefasssystem,' project B4). K.M. is recipient of a Novartis Research Scholarship Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00134-003-1900-2.

Monocyte-endothelium interaction is a fundamental process in many acute and chronic inflammatory diseases. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are fish oil-derived alternative ([omega]-3) precursor fatty acids implicated in the suppression of inflammatory events. We investigated their influence on rolling and adhesion of monocytes to human umbilical vein endothelial cells (HUVEC) under laminar flow conditions in vitro. Exposure of HUVEC to tumor necrosis factor (TNF-[alpha]) strongly increased 1) surface expression of intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and E-selectin, 2) platelet-activating factor (PAF) synthesis as assessed by thrombin challenge, and 3) rate of rolling and adhesion of monocytes. Preincubation of HUVEC with EPA or DHA markedly suppressed PAF synthesis, monocyte rolling, and adherence, whereas expression of endothelial adhesion molecules was unchanged. Also, PAF receptor antagonists markedly suppressed the adhesion rate of monocytes, and EPA or DHA revealed no additional inhibitory capacity. In contrast, arachidonic acid partially reversed the effect of the antagonist. We conclude that [omega]-3 fatty acids suppress rolling and adherence of monocytes on activated endothelial cells in vitro by affecting endothelial PAF generation. eicosapentaenoic acid; arachidonic acid; adhesion molecules; leukocytes; platelet-activating factor

Mayer, Konstantin, Martina Merfels, Marion Muhly Reinholz, Stephanie Gokorsch, Simone Rosseau, Jiirgen Lohmeyer, Nicole Schwarzer, Matthias Kriill, Norbert Suttorp, Friedrich Grimminger, and Werner Seeger.[omega] -3 Fatty acids suppress monocyte adhesion to human endothelial cells: role of endothelial PAF generation. Am J Physiol Heart Circ Physiol 283: H811-818, 2003; 10.1152/ ajpheart.00235.2002.-Monocyte-endothelium interaction is a fundamental process in many acute and chronic inflammatory diseases. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are fish oil-derived alternative ([omega]-3) precursor fatty acids implicated in the suppression of inflammatory events. We investigated their influence on rolling and adhesion of monocytes to human umbilical vein endothelial cells (HUVEC) under laminar flow conditions in vitro. Exposure of HUVEC to tumor necrosis factor (TNF-[alpha]) strongly increased 1) surface expression of intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), and E-selectin, 2) platelet-activating factor (PAF) synthesis as assessed by thrombin challenge, and 3) rate of rolling and adhesion of monocytes. Preincubation of HUVEC with EPA or DHA markedly suppressed PAF synthesis, monocyte rolling, and adherence, whereas expression of endothehal adhesion molecules was unchanged. Also, PAF receptor antagonists markedly suppressed the adhesion rate of monocytes, and EPA or DHA revealed no additional inhibitory capacity. In contrast, arachidonic acid partially reversed the effect of the antagonist. We conclude that [omega]-3 fatty acids suppress rolling and adherence of monocytes on activated endothelial cells in vitro by affecting endothelial PAF generation.