MEDIUM-CHAIN TRIGLYCERIDE SUPPLEMENTATION EXACERBATES PERITONITIS-INDUCED SEPTIC SHOCK IN RATS: ROLE ON CELL MEMBRANE REMODELING Julie Boisrame ´ -Helms,* † Amissi Said, ‡ Me ´ lanie Burban, ‡ Xavier Delabranche,* Laure Stiel,* § Fatiha Zobairi, § Michel Hasselmann,* Vale ´ rie Schini-Kerth, ‡ Florence Toti, ‡ and Ferhat Meziani* † *Service de Re ´ animation Me ´ dicale, Nouvel Ho ˆ pital Civil, Ho ˆ pitaux Universitaires de Strasbourg; and † EA 3072, Fe ´de ´ ration de Me ´ decine Translationnelle, Faculte ´ de Me ´ decine, Universite ´ de Strasbourg, Strasbourg; and ‡ Laboratoire de Biophotonique et Pharmacologie, UMR 7213 CNRS, and § SVTT, EA 7293, Faculte ´ de Pharmacie, Universite ´ de Strasbourg, Illkirch, France Received 21 May 2014; first review completed 10 Jun 2014; accepted in final form 1 Aug 2014 ABSTRACT—Background and aims: Lipid emulsions for parenteral nutrition interfere with immunity and may alter the cell plasma membrane and microparticle release, thus modulating their biological effects. Our aim was to evaluate the effect of two lipid emulsions for parenteral nutrition containing either a mixture of long- and medium-chain triglycerides (LCTs and MCTs) or LCTs only, to assess their role on microparticle release and acute inflammation during septic shock in rats. Methods and results: Septic rats (cecal ligation and puncture) and sham rats were infused with 5% dextrose or a lipid emulsion during 22 h. After 18 h, rats were resuscitated during 4 h and hemodynamic parameters monitored. Circulating microparticles and their phenotype were measured by prothrombinase assay; heart and aorta were collected for Western blotting and electron paramagnetic resonance measurements. No significant effect of lipid emulsions was observed in sham rats. In septic rats, norepinephrine requirements were increased in MCT/LCT-infused rats compared with 5% dextrose- or LCT-infused rats (2.7 T 0.2 vs. 1.9 T 0.8 and 1.2 T 0.3 2g/kg per minute, respectively; P G 0.05) with increased procoagulant microparticle generation (38.6 T 5.8 vs. 18.8 T 3.1 and 19.2 T 3.0 nM equivalent phosphatidylserine [Eq PhtdSer]; P G 0.05), leukocyte- (17.4 T 3.5 vs. 7.7 T 1.8 and 6.0 T 1.1 nM Eq PhtdSer; P G 0.05), platelet- (13.9 T 2.5 vs. 4.4 T 0.7 and 5.4 T 1.3 nM Eq PhtdSer; P G 0.05), and endothelial-derived microparticles (16.9 T 3.6 vs. 6.4 T 1.4 and 5.6 T 0.8 nM Eq PhtdSer; P G 0.05). The mixture of MCTs/LCTs significantly increased cardiac and vascular nitric oxide and superoxide anion production, phos- phorylated I.B, and cyclooxygenase 2 expression compared with the lipid emulsion containing only LCTs. Conclusions: Compared with 5% dextrose, MCT/LCT supplementation during septic shock in rats induced deleterious effects with increased inflammation and cell activation, associated to vascular hyporeactivity. During septic shock, LCT supplementation seemed to be neutral compared with 5% dextrose infusion. KEYWORDS—Lipid emulsions, parenteral nutrition, membrane remodeling, inflammation, microparticles, septic shock INTRODUCTION Fatty acids (FAs) are known to interfere with many physio- logical processes, including inflammation and immunity (1). In- flammatory response modulation in critically ill patients through the modulation of lipid content in parenteral emulsion has therefore aroused clinician interest (2). The composition of lipid emulsions may account for changes in cell membrane composition, downstream production of eicosanoids and cy- tokines, and gene expression (1, 3). Exogenous lipids could alter the cell membrane fluidity and the lipid raft organization, thereby interfering with the activity of key membrane proteins involved in immune cell signaling (4). Several experimental studies have evidenced the regulatory role of lipid rafts after incorporation of n-3 polyunsaturated FAs (PUFAs) that limited T-cell activation and the immune response (5Y7). The n-6 and n-3 PUFA content of immune cell plasma membranes can be modulated by eicosapentaenoic and docosahexaenoic acid in- take (3). Interestingly, n-6 PUFA ingestion may acutely alter the endothelial function, resulting in an increased generation of circulating endothelial microparticles (MPs) (8). Micropar- ticles are plasma membrane submicron vesicles, released from the cell in response to inflammatory signals following the translocation of procoagulant phosphatidylserine (PhtdSer) in the outer leaflet (9). Numerous experimental studies have also demonstrated that MPs behave as vascular and cellular effec- tors (10, 11). In sepsis, circulating MPs may indeed promote inflammation and vascular cell apoptosis and contribute to he- modynamic dysfunction, coagulation activation, and multiple or- gan failure (10, 12). The purpose of this study was therefore to assess the effects of two parenteral nutrition lipid emulsions on the modulation of inflammation, procoagulant MP release, and hemodynamic during septic shock in rats. MATERIALS AND METHODS This study was performed with the approval of the Strasbourg Regional Committee of Ethics in Animal Experimentation (CREMEAS, AL/69/76/02/13). Address reprint requests to: Ferhat Meziani, MD, PhD, Service de Re ´animation Me ´dicaleYNouvel Ho ˆpital Civil, 1, place de l_Ho ˆpital, F-67091 Strasbourg cedex, France. E-mail: ferhat.meziani@chru-strasbourg.fr. This work has been supported by the Alsacian Association for Respiratory Failure Help at Home (Association Des Insuffisants Respiratoires Alsace Lorraine) and the Association for Research Development in Intensive Care (Association pour le De ´veloppement de la Recherche En Re ´animation). The authors have no conflicts of interest to report. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal_s Web site (www.shockjournal.com). DOI: 10.1097/SHK.0000000000000255 Copyright Ó 2014 by the Shock Society 548 SHOCK, Vol. 42, No. 6, pp. 548Y553, 2014 Copyright © 2014 by the Shock Society. Unauthorized reproduction of this article is prohibited.