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      A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome

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          Abstract

          Background

          Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury.

          Methods

          We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up.

          Results

          Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1–7) and angiotensin-(1–5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score.

          Conclusions

          GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes.

          Trial registration

          ClinicalTrials.gov, NCT01597635. Registered on 26 January 2012.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13054-017-1823-x) contains supplementary material, which is available to authorized users.

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          Most cited references27

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          Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system.

          Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1-7). Thus, the axis formed by ACE2/Ang-(1-7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT(1) receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1-7) and Mas with AT(1) and AT(2) receptors.
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            Angiotensin II and renal fibrosis.

            Angiotensin (Ang) II, the main peptide of the renin angiotensin system (RAS), is a renal growth factor, inducing hyperplasia/hypertrophy depending on the cell type. This vasoactive peptide activates mesangial and tubular cells and interstitial fibroblasts, increasing the expression and synthesis of extracellular matrix proteins. Some of these effects seem to be mediated by the release of other growth factors, such as TGF-beta. In experimental models of kidney damage, renal RAS activation, cell proliferation, and upregulation of growth factors and matrix production were described. In some of these models, blockade of Ang II actions by ACE inhibitors and angiotensin type 1 (AT(1)) antagonists prevents proteinuria, gene expression upregulation, and fibrosis, as well as inflammatory cell infiltration. Interestingly, Ang II could also be involved in the fibrotic process because of its behavior as a proinflammatory cytokine, participating in various steps of the inflammatory response: Ang II (1) activates mononuclear cells and (2) increases proinflammatory mediators (cytokines, chemokines, adhesion molecules, nuclear factor kappaB). Finally, Ang II also regulates matrix degradation. These data show that drugs controlling this complex vasoactive peptide are probably one of the best ways of avoiding fibrosis in progressive renal diseases.
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              The role of ACE2 in cardiovascular physiology.

              The renin-angiotensin system (RAS) is critically involved in cardiovascular and renal function and in disease conditions, and has been shown to be a far more complex system than initially thought. A recently discovered homologue of angiotensin-converting enzyme (ACE)--ACE2--appears to negatively regulate the RAS. ACE2 cleaves Ang I and Ang II into the inactive Ang 1-9 and Ang 1-7, respectively. ACE2 is highly expressed in kidney and heart and is especially confined to the endothelium. With quantitative trait locus (QTL) mapping, ACE2 was defined as a QTL on the X chromosome in rat models of hypertension. In these animal models, kidney ACE2 messenger RNA and protein expression were markedly reduced, making ACE2 a candidate gene for this QTL. Targeted disruption of ACE2 in mice failed to elicit hypertension, but resulted in severe impairment in myocardial contractility with increased angiotensin II levels. Genetic ablation of ACE in the ACE2 null mice rescued the cardiac phenotype. These genetic data show that ACE2 is an essential regulator of heart function in vivo. Basal renal morphology and function were not altered by the inactivation of ACE2. The novel role of ACE2 in hydrolyzing several other peptides-such as the apelin peptides, opioids, and kinin metabolites-raises the possibility that peptide systems other than angiotensin and its derivatives also may have an important role in regulating cardiovascular and renal function.
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                Author and article information

                Contributors
                khana@ohsu.edu
                cody.j.benthin@kp.org
                bzeno@remdavis.com
                tealbertson@ucdavis.edu
                john.boyd@hli.ubc.ca
                jchristi@exchange.upenn.edu
                r.i.hall@dal.ca
                gpoirier72@hotmail.com
                juan.ronco@vch.ca
                mark.tidswell@baystatehealth.org
                kelly.2.hardes@gsk.com
                william.m.powley@gsk.com
                tracey.j.wright@gsk.com
                sarah.k.siederer@gsk.com
                dave.a.fairman@gsk.com
                david.a.lipson@gsk.com
                andrew.i.bayliffe@gsk.com
                610-270-4026 , aili.l.lazaar@gsk.com
                Journal
                Crit Care
                Critical Care
                BioMed Central (London )
                1364-8535
                1466-609X
                7 September 2017
                7 September 2017
                2017
                : 21
                : 234
                Affiliations
                [1 ]ISNI 0000 0000 9758 5690, GRID grid.5288.7, Div. of Pulmonary & Critical Care Medicine, Department of Medicine, , Oregon Health & Science University, ; Portland, OR USA
                [2 ]ISNI 0000 0004 0452 6034, GRID grid.415981.0, Riverside Methodist Hospital, ; Columbus, OH USA
                [3 ]School of Medicine, University of California, Davis, Sacramento, CA USA
                [4 ]ISNI 0000 0000 8589 2327, GRID grid.416553.0, St. Paul’s Hospital, ; Vancouver, BC Canada
                [5 ]ISNI 0000 0004 1936 8972, GRID grid.25879.31, Division of Pulmonary, Allergy, and Critical Care Medicine, , University of Pennsylvania School of Medicine, ; Philadelphia, PA USA
                [6 ]ISNI 0000 0004 4689 2163, GRID grid.458365.9, Nova Scotia Health Authority and Dalhousie University, ; Halifax, NS Canada
                [7 ]ISNI 0000 0000 9064 6198, GRID grid.86715.3d, Charles LeMoyne Hospital, Sherbrooke University, ; Greenfield Park, QC Canada
                [8 ]ISNI 0000 0001 2288 9830, GRID grid.17091.3e, Critical Care Medicine, , Vancouver General Hospital, University of British Columbia, ; Vancouver, BC Canada
                [9 ]ISNI 0000 0004 0433 813X, GRID grid.281162.e, Division of Pulmonary and Critical Care, Department of Medicine, , Baystate Medical Center, ; Springfield, MA USA
                [10 ]GlaxoSmithKline R&D, Stockley Park, UK
                [11 ]GlaxoSmithKline R&D, Stevenage, UK
                [12 ]ISNI 0000 0004 0393 4335, GRID grid.418019.5, GlaxoSmithKline R&D, ; King of Prussia, PA USA
                Article
                1823
                10.1186/s13054-017-1823-x
                5588692
                28877748
                06786a16-4958-4dff-bd44-cd4bf8b68fbd
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 13 March 2017
                : 22 August 2017
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Emergency medicine & Trauma
                angiotensin-converting enzyme 2,acute lung injury,respiratory distress syndrome,adult,acute respiratory failure,renin-angiotensin system,humans,interleukin-6

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