Reduced Plasma Nonesterified Fatty Acid Levels and the Advent of an Acute Lung Injury in Mice after Intravenous or Enteral Oleic Acid Administration

Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets

Reduced Plasma Nonesterified Fatty Acid Levels and the Advent of an Acute Lung Injury in Mice after Intravenous or Enteral Oleic Acid Administration

Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturatedfatty-acid-enriched diets

Oleic acid inhibits lung Na/K-ATPase in mice and induces injury with lipid body formation in leukocytes and eicosanoid production

Submitted by sandra infurna ([email protected]) on 2016-01-26T11:43:07Z No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2013.pdf: 2143360 bytes, checksum: 8f5e5674d7c469c0ea089e8c27de22ed (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-01-26T12:03:05Z (GMT) No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2013.pdf: 2143360 bytes, checksum: 8f5e5674d7c469c0ea089e8c27de22ed (MD5)Made available in DSpace on 2016-01-26T12:03:05Z (GMT). No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2013.pdf: 2143360 bytes, checksum: 8f5e5674d7c469c0ea089e8c27de22ed (MD5) Previous issue date: 2013Fundação 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.Universidade Federal do Rio de Janeiro. Departamento de Química Analítica. 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 do Estado do Rio de Janeiro. Faculdade de Ciências Mèdicas. Departamento de Medicina Interna. Rio de Janeiro, RJ, Brasil.Background: Acute respiratory distress syndrome (ARDS) can emerge from certain pathologies, such as sepsis, fat embolism and leptospirosis, in which the levels of unesterified fatty acids are increased in the patient’s plasma. ARDS is characterized by edema formation, and edema resolution occurs mainly due to the pneumocyte Na/K-ATPase activity. As previously described, increased oleic acid (OA) plasma concentrations induce lung injury by interfering with sodium transport. The first aim of this study was to develop a radioactivity-free assay to detect Na,K-ATPase activity ex vivo using a model of OA-induced lung injury in mice. We also investigated the relationship between Na/K-ATPase inhibition and OA-induced lung injury using ouabain-induced lung injury as a comparison, because of the well-described effect of ouabain as a Na/K-ATPase inhibitor. Methods: We developed a Na/K-ATPase assay based on the capture of non-radioactive Rb+ ions by mice lung tissue in the absence or presence of ouabain, a specific Na/K-ATPase inhibitor. Rb+ incorporation into the lung was measured by inductively coupled plasma-optical emission spectrometry (ICP-OES) after lung tissue mineralization. Na/K-ATPase activity was considered as the difference between Rb+ incorporation in the absence and in the presence of ouabain. Bronchoalveolar lavage fluid was collected for lung injury assessment. For this assessment, cell counting, lipid body enumeration and lipid mediator concentrations were measured. Histological analyses were used to determinate lung pathology. Whole body plethysmographic analysis was performed to assay lung function. Results: The lung Na/K-ATPase activity of mice was completely inhibited by an OA dose of 10 μmol, an effect also obtained with 10-3 μmol of ouabain, as demonstrated by the decreased Rb+ incorporation in the lungs. The same OA dose induced lung edema and inflammation with cell influx, lipid body formation, and leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) production. Ouabain also induced lung inflammation, as detected by histological examinations. As far as we know, this is the first time that ouabain-induced lung injury was shown. Both OA and ouabain induced functional lung pathology in mice simultaneously with inhibition of the lung Na/K-ATPase activity. Conclusions: We developed a new non-radioactive assay to quantified Na/K-ATPase in vivo. OA and ouabain inhibited in vivo Na/K-ATPase activity in the lungs and induced lung injury. Our data reinforce the idea that Na/K-ATPase inhibitors may worsen lung injury in specific pathological conditions

The Na/K-ATPase role as a signal transducer in lung inflammation

Acute respiratory distress syndrome (ARDS) is marked by damage to the capillary endothelium and alveolar epithelium following edema formation and cell infiltration. Currently, there are no effective treatments for severe ARDS. Pathologies such as sepsis, pneumonia, fat embolism, and severe trauma may cause ARDS with respiratory failure. The primary mechanism of edema clearance is the epithelial cells’ Na/K-ATPase (NKA) activity. NKA is an enzyme that maintains the electrochemical gradient and cell homeostasis by transporting Na+ and K+ ions across the cell membrane. Direct injury on alveolar cells or changes in ion transport caused by infections decreases the NKA activity, loosening tight junctions in epithelial cells and causing edema formation. In addition, NKA acts as a receptor triggering signal transduction in response to the binding of cardiac glycosides. The ouabain (a cardiac glycoside) and oleic acid induce lung injury by targeting NKA. Besides enzymatic inhibition, the NKA triggers intracellular signal transduction, fostering proinflammatory cytokines production and contributing to lung injury. Herein, we reviewed and discussed the crucial role of NKA in edema clearance, lung injury, and intracellular signaling pathway activation leading to lung inflammation, thus putting the NKA as a protagonist in lung injury pathology

Latin American registry of renal involvement in COVID-19 disease. The relevance of assessing proteinuria throughout the clinical course

The Latin American Society of Nephrology and Hypertension conducted a prospective cohort, multinational registry of Latin American patients with kidney impairment associated to COVID-19 infection with the objective to describe the characteristics of acute kidney disease under these circumstances. The study was carried out through open invitation in order to describe the characteristics of the disease in the region. Eight-hundred and seventy patients from 12 countries were included. Median age was 63 years (54–74), most of patients were male (68.4%) and with diverse comorbidities (87.2%). Acute kidney injury (AKI) was hospital-acquired in 64.7% and non-oliguric in 59.9%. Multiorgan dysfunction syndrome (MODS) due to COVID-19 and volume depletion were the main factors contributing to AKI (59.2% and 35.7% respectively). Kidney replacement therapy was started in 46.2%. Non-recovery of renal function was observed in 65.3%. 71.5% of patients were admitted to ICU and 72.2% underwent mechanical ventilation. Proteinuria at admission was present in 62.4% of patients and proteinuria during hospital-stay occurred in 37.5%. Those patients with proteinuria at admission had higher burden of comorbidities, higher baseline sCr, and MODS was severe. On the other hand, patients with de novo proteinuria had lower incidence of comorbidities and near normal sCr at admission, but showed adverse course of disease. COVID-19 MODS was the main cause of AKI in both groups. All-cause mortality of the general population was 57.4%, and it was associated to age, sepsis as cause of AKI, severity of condition at admission, oliguria, mechanical ventilation, non-recovery of renal function, in-hospital complications and hospital stay. In conclusion, our study contributes to a better knowledge of this condition and highlights the relevance of the detection of proteinuria throughout the clinical course

MUSiC : a model-unspecific search for new physics in proton-proton collisions at root s=13TeV

Results of the Model Unspecific Search in CMS (MUSiC), using proton-proton collision data recorded at the LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), are presented. The MUSiC analysis searches for anomalies that could be signatures of physics beyond the standard model. The analysis is based on the comparison of observed data with the standard model prediction, as determined from simulation, in several hundred final states and multiple kinematic distributions. Events containing at least one electron or muon are classified based on their final state topology, and an automated search algorithm surveys the observed data for deviations from the prediction. The sensitivity of the search is validated using multiple methods. No significant deviations from the predictions have been observed. For a wide range of final state topologies, agreement is found between the data and the standard model simulation. This analysis complements dedicated search analyses by significantly expanding the range of final states covered using a model independent approach with the largest data set to date to probe phase space regions beyond the reach of previous general searches.Peer reviewe

Measurement of prompt open-charm production cross sections in proton-proton collisions at root s=13 TeV

The production cross sections for prompt open-charm mesons in proton-proton collisions at a center-of-mass energy of 13TeV are reported. The measurement is performed using a data sample collected by the CMS experiment corresponding to an integrated luminosity of 29 nb(-1). The differential production cross sections of the D*(+/-), D-+/-, and D-0 ((D) over bar (0)) mesons are presented in ranges of transverse momentum and pseudorapidity 4 < p(T) < 100 GeV and vertical bar eta vertical bar < 2.1, respectively. The results are compared to several theoretical calculations and to previous measurements.Peer reviewe

Search for new particles in events with energetic jets and large missing transverse momentum in proton-proton collisions at root s=13 TeV

A search is presented for new particles produced at the LHC in proton-proton collisions at root s = 13 TeV, using events with energetic jets and large missing transverse momentum. The analysis is based on a data sample corresponding to an integrated luminosity of 101 fb(-1), collected in 2017-2018 with the CMS detector. Machine learning techniques are used to define separate categories for events with narrow jets from initial-state radiation and events with large-radius jets consistent with a hadronic decay of a W or Z boson. A statistical combination is made with an earlier search based on a data sample of 36 fb(-1), collected in 2016. No significant excess of events is observed with respect to the standard model background expectation determined from control samples in data. The results are interpreted in terms of limits on the branching fraction of an invisible decay of the Higgs boson, as well as constraints on simplified models of dark matter, on first-generation scalar leptoquarks decaying to quarks and neutrinos, and on models with large extra dimensions. Several of the new limits, specifically for spin-1 dark matter mediators, pseudoscalar mediators, colored mediators, and leptoquarks, are the most restrictive to date.Peer reviewe

Combined searches for the production of supersymmetric top quark partners in proton-proton collisions at root s=13 TeV

A combination of searches for top squark pair production using proton-proton collision data at a center-of-mass energy of 13 TeV at the CERN LHC, corresponding to an integrated luminosity of 137 fb(-1) collected by the CMS experiment, is presented. Signatures with at least 2 jets and large missing transverse momentum are categorized into events with 0, 1, or 2 leptons. New results for regions of parameter space where the kinematical properties of top squark pair production and top quark pair production are very similar are presented. Depending on themodel, the combined result excludes a top squarkmass up to 1325 GeV for amassless neutralino, and a neutralinomass up to 700 GeV for a top squarkmass of 1150 GeV. Top squarks with masses from 145 to 295 GeV, for neutralino masses from 0 to 100 GeV, with a mass difference between the top squark and the neutralino in a window of 30 GeV around the mass of the top quark, are excluded for the first time with CMS data. The results of theses searches are also interpreted in an alternative signal model of dark matter production via a spin-0 mediator in association with a top quark pair. Upper limits are set on the cross section for mediator particle masses of up to 420 GeV

Development and validation of HERWIG 7 tunes from CMS underlying-event measurements

This paper presents new sets of parameters (“tunes”) for the underlying-event model of the HERWIG7 event generator. These parameters control the description of multiple-parton interactions (MPI) and colour reconnection in HERWIG7, and are obtained from a fit to minimum-bias data collected by the CMS experiment at s=0.9, 7, and 13Te. The tunes are based on the NNPDF 3.1 next-to-next-to-leading-order parton distribution function (PDF) set for the parton shower, and either a leading-order or next-to-next-to-leading-order PDF set for the simulation of MPI and the beam remnants. Predictions utilizing the tunes are produced for event shape observables in electron-positron collisions, and for minimum-bias, inclusive jet, top quark pair, and Z and W boson events in proton-proton collisions, and are compared with data. Each of the new tunes describes the data at a reasonable level, and the tunes using a leading-order PDF for the simulation of MPI provide the best description of the dat