Omega-9 Oleic Acid, the Main Compound of Olive Oil, Mitigates Inflammation during Experimental Sepsis

The Mediterranean diet, rich in olive oil, is beneficial, reducing the risk of cardiovascular diseases and cancer. Olive oil is mostly composed of the monounsaturated fatty acid omega-9. We showed omega-9 protects septic mice modulating lipid metabolism. Sepsis is initiated by the host response to infection with organ damage, increased plasma free fatty acids, high levels of cortisol, massive cytokine production, leukocyte activation, and endothelial dysfunction. We aimed to analyze the effect of omega-9 supplementation on corticosteroid unbalance, inflammation, bacterial elimination, and peroxisome proliferator-activated receptor (PPAR) gamma expression, an omega-9 receptor and inflammatory modulator. We treated mice for 14 days with omega-9 and induced sepsis by cecal ligation and puncture (CLP). We measured systemic corticosterone levels, cytokine production, leukocyte and bacterial counts in the peritoneum, and the expression of PPAR gamma in both liver and adipose tissues during experimental sepsis. We further studied omega-9 effects on leukocyte rolling in mouse cremaster muscle-inflamed postcapillary venules and in the cerebral microcirculation of septic mice. Here, we demonstrate that omega-9 treatment is associated with increased levels of the anti-inflammatory cytokine IL-10 and decreased levels of the proinflammatory cytokines TNF-alpha and IL-1 beta in peritoneal lavage fluid of mice with sepsis. Omega-9 treatment also decreased systemic corticosterone levels. Neutrophil migration from circulation to the peritoneal cavity and leukocyte rolling on the endothelium were decreased by omega-9 treatment. Omega-9 also decreased bacterial load in the peritoneal lavage and restored liver and adipose tissue PPAR gamma expression in septic animals. Our data suggest a beneficial anti-inflammatory role of omega-9 in sepsis, mitigating leukocyte rolling and leukocyte influx, balancing cytokine production, and controlling bacterial growth possibly through a PPAR gamma expression-dependent mechanism. The significant reduction of inflammation detected after omega-9 enteral injection can further contribute to the already known beneficial properties facilitated by unsaturated fatty acid-enriched diets

Omega-9 Oleic Acid Induces Fatty Acid Oxidation and Decreases Organ Dysfunction and Mortality in Experimental Sepsis

Submitted by sandra infurna ([email protected]) on 2016-06-19T21:56:40Z No. of bitstreams: 1 flora_oliveira_etal_IOC_2016.PDF: 1127513 bytes, checksum: 2b33c8a8ebdd6279e2e149aaedca5a3a (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-06-19T22:20:25Z (GMT) No. of bitstreams: 1 flora_oliveira_etal_IOC_2016.PDF: 1127513 bytes, checksum: 2b33c8a8ebdd6279e2e149aaedca5a3a (MD5)Made available in DSpace on 2016-06-19T22:20:25Z (GMT). No. of bitstreams: 1 flora_oliveira_etal_IOC_2016.PDF: 1127513 bytes, checksum: 2b33c8a8ebdd6279e2e149aaedca5a3a (MD5) Previous issue date: 2016Made available in DSpace on 2016-07-08T12:22:05Z (GMT). No. of bitstreams: 3 flora_oliveira_etal_IOC_2016.PDF.txt: 55221 bytes, checksum: 6263327453588b424db910e20fddf55b (MD5) flora_oliveira_etal_IOC_2016.PDF: 1127513 bytes, checksum: 2b33c8a8ebdd6279e2e149aaedca5a3a (MD5) license.txt: 2991 bytes, checksum: 5a560609d32a3863062d77ff32785d58 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal Fluminense. Faculdade de Ciências Médicas. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade do Estado do Rio de Janeiro. Faculdade de Ciências Médicas. Departamento de Medicina Interna. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil / Universidade Estácio de Sá. Programa de Produtividade Científica. Rio de Janeiro, RJ, Brasil .Sepsis is characterized by inflammatory and metabolic alterations, which lead to massive cytokine production, oxidative stress and organ dysfunction. In severe systemic inflammatory response syndrome, plasma non-esterified fatty acids (NEFA) are increased. Several NEFA are deleterious to cells, activate Toll-like receptors and inhibit Na+/K+-ATPase, causing lung injury. A Mediterranean diet rich in olive oil is beneficial. Themain component of olive oil is omega-9 oleic acid (OA), a monounsaturated fatty acid (MUFA).We analyzed the effect of OA supplementation on sepsis. OA ameliorated clinical symptoms, increased the survival rate, prevented liver and kidney injury and decreased NEFA plasma levels inmice subjected to cecal ligation and puncture (CLP). OA did not alter food intake and weight gain but diminished reactive oxygen species (ROS) production and NEFA plasma levels. Carnitine palmitoyltransferase IA (CPT1A) mRNA levels were increased, while uncoupling protein 2 (UCP2) liver expression was enhanced in mice treated with OA. OA also inhibited the decrease in 5' AMPactivated protein kinase (AMPK) expression and increased the enzyme expression in the liver of OA-treated mice compared to septic animals.We showed that OA pretreatment decreased NEFA concentration and increased CPT1A and UCP2 and AMPK levels, decreasing ROS production.We suggest that OA has a beneficial role in sepsis by decreasing metabolic dysfunction, supporting the benefits of diets high inmonounsaturated fatty acids (MUFA)

Simvastatin Posttreatment Controls Inflammation and Improves Bacterial Clearance in Experimental Sepsis

Sepsis is characterized by a life-threatening organ dysfunction caused by an unbalanced host response to microbe infection that can lead to death. Besides being currently the leading cause of death in intensive care units worldwide, sepsis can also induce long-term consequences among survivors, such as cognitive impairment. Statins (lipid-lowering drugs widely used to treat dyslipidemia) have been shown to possess pleiotropic anti-inflammatory and antimicrobial effects. These drugs act inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the limiting step in cholesterol biosynthesis. In this work, we evaluated the therapeutic effects of simvastatin in an animal model of sepsis. In previous study from our group, statin pretreatment avoided cognitive damage and neuroinflammation in sepsis survivors. Herein, we focused on acute inflammation where sepsis was induced by cecal ligation and puncture (CLP), and the animals were treated with simvastatin (2 mg/kg) 6 h after surgery. We measured plasma biochemical markers of organ dysfunction, cell migration, cell activation, bacterial elimination, production of nitric oxide 24 h after CLP, survival rate for 7 days, and cognitive impairment 15 days after CLP. One single administration of simvastatin 6 h after CLP was able to prevent both liver and kidney dysfunction. In addition, this drug decreased cell accumulation in the peritoneum as well as the levels of TNF-α, MIF, IL-6, and IL-1β. Simvastatin diminished the number of bacterial colony forming units (CFU) and increased the production of nitric oxide production in the peritoneum. Simvastatin treatment increased survival for the first 24 h, but it did not alter survival rate at the end of 7 days. Our results showed that posttreatment with simvastatin hampered organ dysfunction, increased local production of nitric oxide, improved bacterial clearance, and modulated inflammation in a relevant model of sepsis

Na/K-ATPase assay in the intact mice lung subjected to perfusion

Made available in DSpace on 2015-05-27T13:39:50Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) adriana_silvaetal_IOC_2014.pdf: 350633 bytes, checksum: 5135d467f38c8b0fb3cbe9daca32f22b (MD5) Previous issue date: 2014Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal Fluminense. Instituto de Biologia. Departamento de Biologia Celular e Molecular. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Departamento de Reativos para Diagnóstico. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Bio-Manguinhos. Departamento de Reativos para Diagnóstico. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Departamento de Química Analítica. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Departamento de Química Analítica. Rio de Janeiro, RJ, Brasil.Among the characteristics of acute respiratory distress syndrome (ARDS) is edema formation and its resolution depends on pneumocyte Na/K-ATPase activity. Increased concentration of oleic acid (OA) in plasma induces lung injury by targeting Na/K-ATPase and, thus, interfering in sodium transport. FINDINGS: Presently, we adapted a radioactivity-free assay to detect Na/K-ATPase activity in perfused lung mice, comparing the inhibitory effect of ouabain and OA. We managed to perfuse only the lung, avoiding the systemic loss of rubidium. Rb+ incorporation into lung was measured by inductively coupled plasma optical emission spectrometry (ICP OES) technique, after lung tissue digestion. Na/K-ATPase activity was the difference between Rb+ incorporation with or without ouabain. Lung Na/K-ATPase was completely inhibited by perfusion with ouabain. However, OA caused a partial inhibition. CONCLUSIONS: In the present work the amount of incorporated Rb+ was greater than seen in our previous report, showing that the present technique is trustworthy. This new proposed assay may allow researchers to study the importance of Na/K-ATPase activity in lung pathophysiology

Oleic acid increases the transcription of the CPT1A gene in septic mice.

<p>Swiss mice were treated for 14 days with oleic acid. On the 15^th day, mice were subjected to CLP. The liver was removed 24 hours after CLP. CPT1A mRNA was detected by RT-PCR. A representative gel of (A) CPT1A and of the (B) control GAPDH gene transcription. The loading control was GAPDH. (C)The bands were analyzed by densitometry and are represented as the CPT1A/GAPDH ratio. Values represent mean and SEM from 5–6 animals per group.</p

Oleic acid treatment decreases MDA formation, and induces UCP2 and AMPK in septic mice.

<p>Mice were treated for 14 days with oleic acid, and on the 15^th day, CLP was performed. The liver was removed 24 hours after CLP for analysis of (A) MDA and (B) UCP2 by western blotting. The graph shows the densitometric analysis of the UCP2, AMPK and β-actin bands, as described in the methods. The results are expressed as the mean <i>±</i> SEM of 5–6 animals. (* and +) p < 0.05 compared to sham and sham + OA (respectively) and (#) compared to CLP.</p

Oleic Acid Induces Lung Injury in Mice through Activation of the ERK Pathway

Oleic acid (OA) can induce acute lung injury in experimental models. In the present work, we used intratracheal OA injection to show augmented oedema formation, cell migration and activation, lipid mediator, and cytokine productions in the bronchoalveolar fluids of Swiss Webster mice. We also demonstrated that OA-induced pulmonary injury is dependent on ERK1/2 activation, since U0126, an inhibitor of ERK1/2 phosphorylation, blocked neutrophil migration, oedema, and lipid body formation as well as IL-6, but not IL-1β production. Using a mice strain carrying a null mutation for the TLR4 receptor, we proved that increased inflammatory parameters after OA challenges were not due to the activation of the TLR4 receptor. With OA being a Na/K-ATPase inhibitor, we suggest the possible involvement of this enzyme as an OA target triggering lung inflammation

Plasma NEFA concentrations are reduced after oleic acid treatment in septic animals.

<p>Mice were treated for 14 days with oleic acid. On the 15^th day, mice were subjected to CLP. Twenty-four hours after CLP, blood was collected for albumin quantification. (A)Total NEFA concentration (sum of average concentrations of the five NEFA) 24 hours after CLP in OA-treated and untreated animals. (B) Plasma concentrations of palmitoleic, linoleic, palmitic, oleic and stearic acids. (C) Plasma albumin levels. (D) Ratio of serum NEFA and albumin. Values represent the mean <i>±</i> SEM of at least 5 animals. (Total NEFA and single fatty acid: sham = 7 animals, sham + OA = 5 animals, CLP = 6 animals and CLP + OA = 8 animals; Albumin and ratio of serum NEFA and albumin: sham = 5 animals, sham + OA = 6 animals, CLP = 5 animals and CLP + OA = 6 animals). The results are representative of 3 independent experiments. p < 0.05 * CLP vs sham, # CLP vs CLP plus oleic acid.</p