Apelin; ACE2 and Biomarkers of Alveolar-capillary Permeability in SARS-cov-2 (COVID-19). (APEL-COVID)

Hypothesis: The apelin/APJ system is involved in the protection of the lung affected by the COVID-19 by interacting with the SARS-coV-2 entry door: the Angiotensin I Converting Enzyme 2 (ACE2) and the renin-angiotensin system (ras). Elevated systemic levels of apelins and ACE2 activity are associated to less critical forms of COVID-19 and characterized by less pulmonary hyperpermeability and inflammation.

Goals: Main: In COVID-19+ patients, to establish the basic knowledge of 1) apelins and related systems (ras and degradation enzymes, of which ACE2) pheno-dynamic profile in bloodstream, 2) pulmonary hyperpermeability profile by biomarker's assessment i) comparison of SARS vs. lesser COVID-19 respiratory injury, and with non COVID-19 ARDS and non ARDS acute respiratory condition. Secondary: To set up links between basic and progressive clinical data (data collection system APEL-COVID).

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Diagnostic test: COVID-19 test; Diagnostic test: Blood sampling

Detailed Description

COVID-19 affects patients by it's entry way: the airways and the deep lung. 20 to 30% of symptomatic adult patients which are hospitalised in or out of the intensive care unit exhibit respiratory distress with major oxygenation index alterations. That syndrome is specifically designated severe acute respiratory syndrome coronavirus 2 (SARS-coV-2). SARS-coV-2 develops 2 weeks after the symptoms start, with a recurring fever, progressing dyspnea and a mortality rate of 10 to 50%. In SARS-coV-2: 1) radiological pulmonary infiltrates are more peripheral and 2) dominancy of hyperinflammation (cytokine storm, of which the interleukine-6 IL-6) and hyperpermeability of the alveolar-capillary barrier is observed, 3) in comparison to a traditional (non COVID) ARDS, the hypoxia generated is exceptionally severe and associated to a pulmonary compliance sparsely reduce in more than 70% of cases.

The Angiotensin I Converting Enzyme 2 (ACE2) is a transmembrane carboxypeptidase of the renin-angiotensin system (ras) implicated in cardiovascular homeostasis. ACE2 counter-regulates the proinflammatory hypertensive ACE1/Angiotensin II (Ang II). ACE2 converts Ang II in Ang1-7 to promote vasodilation, anti-inflammation and tissular protection. ACE2 is expressed abundantly in the lung and is the entry door for many virus like the influenza A, coV-1 and -2. A downregulation of ACE2 activity leads to Ang II excess, with a stimulation of the AngI receptor (AT1R) and an increase of pulmonary vascular permeability, negatively impacting the prognosis of the influenza virus H7N9. More than 85% of pulmonary ACE2 is expressed in apical membrane of alveolar epithelial cell type II (AECII) which are located in the lung distal air spaces at the alveolar-capillary barrier interface. This is where the coV-2 set up and induces the SARS (COVID-19+). AECII regulate the alveolar-capillary barrier permeability. Those produce specific proteins (SP-D or surfactant protein D, and CC-16 or Clara Cell protein) which are released in bloodstream when the alveolar-capillary barrier becomes hyperpermeable and are diagnostic and prognostic biological markers.

The apelin/APJ system could be a protective way by interacting with the renin-angiotensin system (ras) and Angiotensin I Converting Enzyme 2 (ACE2). The apelin/APJ system is recognized to protect and optimize cardiovascular functions. The apelins and receptor APJ operate independently of the catecholaminergic system and constitute a counter regulatory response to the vasopressinergic way with an inodilator activity. The apelin/APJ is largely expressed in the lung and is involved in the reduction of pulmonary inflammation. Apelin-13 stabilizes the mitochondrial function, reduces membrane permeability, prevents apoptosis and stimulates AECII proliferation. The apelin/APJ is reactive to hypoxia like in SARS or ARDS with an increase of blood apelins levels. Apelins are substrates for the ras system and kallikrein/kinin which are producing degradation enzymes like ACE2. Despite this, apelins can reverse a decreased activity of ACE2, and regulate the overproduction of Ang II and the AT1R stimulation which lead to an increase pulmonary vascular permeability and lung edema. APJ is also able to inhibit AT1R by trans-allosteric combination. APJ is a co-receptor for the human and simian immunodeficiency virus, and the apelins block their entry. The proximity between ACE2 and APJ on AECII membranes and their internalization/degradation management in term of the apelins isoform lead to the query of their interaction and the link with their pulmonary protective activity.

Hypothesis: The apelin/APJ system is involved in the protection of the lung affected by the COVID-19 by interacting with the SARS-coV-2 entry door: the Angiotensin I Converting Enzyme 2 (ACE2) and the renin-angiotensin system (ras). Elevated systemic levels of apelins and ACE2 activity are associated to less critical forms of COVID-19 and characterized by less pulmonary hyperpermeability and inflammation.

Goals: Main: In COVID-19+ patients, to establish the basic knowledge of 1) apelins and related systems (ras and degradation enzymes, of which ACE2) pheno-dynamic profile in bloodstream, 2) pulmonary hyperpermeability profile by biomarker's assessment i) comparison of SARS vs. lesser COVID-19 respiratory injury, and with non COVID-19 ARDS and non ARDS acute respiratory condition. Secondary: To set up links between basic and progressive clinical data (data collection system APEL-COVID).

Methods: Observational pilot study of a prospective cohort recruiting in the 36 hours after admission adult patients hospitalized for a symptomatic acute respiratory illness. Groups: 1) COVID+, SARS, MV+ (mechanical ventilation) or not, with more than 6L/min-40% FiO2 for a SpO2 more than 90% for more than 24hrs (n=30); 2) COVID+, non SARS, MV-, with less than 6L/min-40% FiO2 for a SpO2 more than 90% for more than 24hrs (n=30); 3) COVID-, ARDS, MV+, with more than 6L/min-40% FiO2 for a SpO2 more than 90% for more than 24hrs (n=30); 4) COVID-, non ARDS, MV-, with less than 6L/min-40% FiO2 for a SpO2 more than 90% for more than 24hrs (n=30). Given the effects of the pressure generated by mechanical ventilation on epithelial biological markers, 2 sub-groups of 10 controls patients hospitalized for non-respiratory reasons will be constituted post hoc with sex-age matching to the above groups. The patients COVID+ non SARS will be respiratory symptomatic, with or without lung infiltrates and needs in O2 less than 6L/min-40% FiO2 for a SpO2 more than 90% and hospitalized on floors of the pulmonology or internal medicine or in the intensives cares units. The ARDS patients will be selected in the direct form (e.g. pneumonia, aspiration) and the oxygenation index parameters established by Berlin definition.

• Study Type: Observational
• Enrollment (Actual): 140

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Sherbrooke, Quebec, Canada, J1H5N4
      • Sherbrooke University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients hospitalized on floors (pulmonology or in internal medecine) or in intensive care units of the Sherbrooke hospital/CHUS and patients hospitalized in intensive care units of the Angers hospital/CHUA.

Description

Inclusion Criteria:

• For the 4 -non-control- major groups:
• Adults patients hospitalized for symptomatic acute (presumably infectious) respiratory illness
• In the 36 hours after admission.

Exclusion Criteria:

• Patients already hospitalized for more than 36 hours.
• Pediatric patients.
• Asymptomatic patients.
• Non acute respiratory illness patients.
• Primary pulmonary embolism as causative (i.e pulmonary embolism can be concomitant to respiratory symptoms related to SRAS COVID but not without).
• Exacerbated terminal/severe COPD of Pulmonary fibrosis with or without home oxygen.
• Patients with indirect form of ARDS.
• Cystic fibrosis.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

6

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
COVID+, SARS; patients COVID+ SARS mechanically ventilated and/or needing more than 6L/min of O2-40% FiO2 for a SpO2 equal or above 90% for more than 24hours.	Diagnostic test: COVID-19 test; Nasal pharyngeal swab; Diagnostic test: Blood sampling; 20cc of blood will be collected each 7 days during 28 days.
COVID+, nonSARS; patients COVID+ nonSARS respiratory symptomatic, with or without lung infiltrates, non mechanically ventilated, and needing less than 6L/min O2-40% FiO2 for a SpO2 equal or above 90%. They are hospitalized on floors (pulmonolgy, internal medecine or in intensives cares units).	Diagnostic test: COVID-19 test; Nasal pharyngeal swab; Diagnostic test: Blood sampling; 20cc of blood will be collected each 7 days during 28 days.
COVID-, ARDS; patients are in ARDS according to the Berlin definition and the lung injury is categorized in the direct form (e.g. pneumonia, aspiration).	Diagnostic test: COVID-19 test; Nasal pharyngeal swab; Diagnostic test: Blood sampling; 20cc of blood will be collected each 7 days during 28 days.
COVID-, nonARDS; patients are not in ARDS according to the Berlin definition but are respiratory symptomatic, with or without lung infiltrates and needing less than 6L O2/min-40% FiO2 for a SpO2 equal or above 90%.	Diagnostic test: COVID-19 test; Nasal pharyngeal swab; Diagnostic test: Blood sampling; 20cc of blood will be collected each 7 days during 28 days.
COVID-, control, MV+; patients hospitalized and mechanically ventilated for non-respiratory reasons (post hoc with sex-age matching).	Diagnostic test: COVID-19 test; Nasal pharyngeal swab; Diagnostic test: Blood sampling; 20cc of blood will be collected each 7 days during 28 days.
COVID-, control, MV-; non mechanically ventilated patients hospitalized for non-respiratory reasons (post hoc with sex-age matching).	Diagnostic test: COVID-19 test; Nasal pharyngeal swab; Diagnostic test: Blood sampling; 20cc of blood will be collected each 7 days during 28 days.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood apelins-13/12, -17/16, -36	Measurement by MS/MS of the blood apelins-13/12, -17/16, -36 each 7 days during 28 days.	28 days
Blood angiotensin II	Measurement by ELISA of the blood angiotensin II each 7 days during 28 days.	28 days
Blood Clara cell protein (CC16)	Measurement by ELISA of the blood CC16 each 7 days during 28 days.	28 days
Blood interleukine-6 (IL-6)	Measurement by ELISA of the blood IL-6 each 7 days during 28 days.	28 days
Blood surfactant protein D (SP-D)	Measurement by ELISA of the blood SP-D each 7 days during 28 days.	28 days
Plasma ACE2 activity measurement by fluorometry	Measurement of the plasma ACE2 activity each 7 days during 28 days.	28 days
Plasma lysyl oxidase activity measurement by fluorometry	Measurement of the plasma lysyl oxidase activity each 7 days during 28 days.	28 days
Plasma neprilysin activity measurement by fluorometry	Measurement of the plasma neprilysin activity each 7 days during 28 days.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
APACHEII	Prognostic score (APACHEII) each day during 28 days.	28 days
Oxygenation index	Oxygenation index each day during 28 days.	28 days
Mechanical ventilation	Duration of the mechanical ventilation.	28 days
Pulmonary compliance (Dynamic, real-time, on ventilator device: Tidal volume / Plateau pressure - PEEP	Measurement of the pulmonary compliance each day during 28 days.	28 days
Length of hospital stay	Measurement of the length of hospital stay and/or mortality in-hospital.	28 days
SOFA	Prognostic score (SOFA) each day during 28 days.	28 days

Collaborators and Investigators

• Sponsor: Centre de recherche du Centre hospitalier universitaire de Sherbrooke
• Collaborators: University Hospital, Angers
• Investigators: Principal Investigator: Olivier Lesur, MD PhD, Sherbrooke University

Publications and helpful links

General Publications

• Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020 Mar 28;395(10229):1054-1062. doi: 10.1016/S0140-6736(20)30566-3. Epub 2020 Mar 11. Erratum In: Lancet. 2020 Mar 28;395(10229):1038. Lancet. 2020 Mar 28;395(10229):1038.
• ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012 Jun 20;307(23):2526-33. doi: 10.1001/jama.2012.5669.
• Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000 May 4;342(18):1334-49. doi: 10.1056/NEJM200005043421806. No abstract available.
• Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 Apr;46(4):586-590. doi: 10.1007/s00134-020-05985-9. Epub 2020 Mar 3. No abstract available.
• Eisner MD, Parsons P, Matthay MA, Ware L, Greene K; Acute Respiratory Distress Syndrome Network. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax. 2003 Nov;58(11):983-8. doi: 10.1136/thorax.58.11.983.
• Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.
• Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005 Aug;11(8):875-9. doi: 10.1038/nm1267. Epub 2005 Jul 10.
• Gattinoni L, Coppola S, Cressoni M, Busana M, Rossi S, Chiumello D. COVID-19 Does Not Lead to a "Typical" Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2020 May 15;201(10):1299-1300. doi: 10.1164/rccm.202003-0817LE. No abstract available.
• Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005 Jul 7;436(7047):112-6. doi: 10.1038/nature03712.
• Sun H, Ning R, Tao Y, Yu C, Deng X, Zhao C, Meng S, Tang F, Xu D. Risk Factors for Mortality in 244 Older Adults With COVID-19 in Wuhan, China: A Retrospective Study. J Am Geriatr Soc. 2020 Jun;68(6):E19-E23. doi: 10.1111/jgs.16533. Epub 2020 May 12.
• Nikpouraghdam M, Jalali Farahani A, Alishiri G, Heydari S, Ebrahimnia M, Samadinia H, Sepandi M, Jafari NJ, Izadi M, Qazvini A, Dorostkar R, Tat M, Shahriary A, Farnoosh G, Hosseini Zijoud SR, Taghdir M, Alimohamadi Y, Abbaszadeh S, Gouvarchin Ghaleh HE, Bagheri M. Epidemiological characteristics of coronavirus disease 2019 (COVID-19) patients in IRAN: A single center study. J Clin Virol. 2020 Jun;127:104378. doi: 10.1016/j.jcv.2020.104378. Epub 2020 Apr 21.
• Zangrillo A, Beretta L, Scandroglio AM, Monti G, Fominskiy E, Colombo S, Morselli F, Belletti A, Silvani P, Crivellari M, Monaco F, Azzolini ML, Reineke R, Nardelli P, Sartorelli M, Votta CD, Ruggeri A, Ciceri F, De Cobelli F, Tresoldi M, Dagna L, Rovere-Querini P, Serpa Neto A, Bellomo R, Landoni G; COVID-BioB Study Group. Characteristics, treatment, outcomes and cause of death of invasively ventilated patients with COVID-19 ARDS in Milan, Italy. Crit Care Resusc. 2020 Apr 23. Online ahead of print.
• Lu W, Zhang S, Chen B, Chen J, Xian J, Lin Y, Shan H, Su ZZ. A Clinical Study of Noninvasive Assessment of Lung Lesions in Patients with Coronavirus Disease-19 (COVID-19) by Bedside Ultrasound. Ultraschall Med. 2020 Jun;41(3):300-307. doi: 10.1055/a-1154-8795. Epub 2020 Apr 15.
• Sayiner A, Cinkooglu A, Tasbakan MS, Basoglu OK, Ceylan N, Savas R, Bayraktaroglu S, Ozhan MH. Radiographic examination of the chest and COVID-19. Ann R Coll Surg Engl. 2020 May;102(5):334. doi: 10.1308/rcsann.2020.0099. No abstract available.
• Wu J, Pan J, Teng D, Xu X, Feng J, Chen YC. Interpretation of CT signs of 2019 novel coronavirus (COVID-19) pneumonia. Eur Radiol. 2020 Oct;30(10):5455-5462. doi: 10.1007/s00330-020-06915-5. Epub 2020 May 4.
• Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, Franceschini F, Airo P, Bazzani C, Beindorf EA, Berlendis M, Bezzi M, Bossini N, Castellano M, Cattaneo S, Cavazzana I, Contessi GB, Crippa M, Delbarba A, De Peri E, Faletti A, Filippini M, Filippini M, Frassi M, Gaggiotti M, Gorla R, Lanspa M, Lorenzotti S, Marino R, Maroldi R, Metra M, Matteelli A, Modina D, Moioli G, Montani G, Muiesan ML, Odolini S, Peli E, Pesenti S, Pezzoli MC, Pirola I, Pozzi A, Proto A, Rasulo FA, Renisi G, Ricci C, Rizzoni D, Romanelli G, Rossi M, Salvetti M, Scolari F, Signorini L, Taglietti M, Tomasoni G, Tomasoni LR, Turla F, Valsecchi A, Zani D, Zuccala F, Zunica F, Foca E, Andreoli L, Latronico N. Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia, Italy. Autoimmun Rev. 2020 Jul;19(7):102568. doi: 10.1016/j.autrev.2020.102568. Epub 2020 May 3.
• van de Veerdonk FL, Netea MG, van Deuren M, van der Meer JW, de Mast Q, Bruggemann RJ, van der Hoeven H. Kallikrein-kinin blockade in patients with COVID-19 to prevent acute respiratory distress syndrome. Elife. 2020 Apr 27;9:e57555. doi: 10.7554/eLife.57555.
• Gralinski LE, Bankhead A 3rd, Jeng S, Menachery VD, Proll S, Belisle SE, Matzke M, Webb-Robertson BJ, Luna ML, Shukla AK, Ferris MT, Bolles M, Chang J, Aicher L, Waters KM, Smith RD, Metz TO, Law GL, Katze MG, McWeeney S, Baric RS. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio. 2013 Aug 6;4(4):e00271-13. doi: 10.1128/mBio.00271-13.
• Herold S, Gabrielli NM, Vadasz I. Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 2013 Nov 15;305(10):L665-81. doi: 10.1152/ajplung.00232.2013. Epub 2013 Sep 13.
• Keidar S, Kaplan M, Gamliel-Lazarovich A. ACE2 of the heart: From angiotensin I to angiotensin (1-7). Cardiovasc Res. 2007 Feb 1;73(3):463-9. doi: 10.1016/j.cardiores.2006.09.006. Epub 2006 Sep 19.
• Gichuhi PM, Isahakia MA. Electron-microscopic localization of baboon acrosomal antigens using antisperm monoclonal antibody. Acta Anat (Basel). 1992;144(2):178-83. doi: 10.1159/000147304.
• Wevers BA, van der Hoek L. Renin-angiotensin system in human coronavirus pathogenesis. Future Virol. 2010 Mar;5(2):145-161. doi: 10.2217/fvl.10.4. Epub 2010 Mar 1.
• Yang P, Gu H, Zhao Z, Wang W, Cao B, Lai C, Yang X, Zhang L, Duan Y, Zhang S, Chen W, Zhen W, Cai M, Penninger JM, Jiang C, Wang X. Angiotensin-converting enzyme 2 (ACE2) mediates influenza H7N9 virus-induced acute lung injury. Sci Rep. 2014 Nov 13;4:7027. doi: 10.1038/srep07027.
• Mossel EC, Wang J, Jeffers S, Edeen KE, Wang S, Cosgrove GP, Funk CJ, Manzer R, Miura TA, Pearson LD, Holmes KV, Mason RJ. SARS-CoV replicates in primary human alveolar type II cell cultures but not in type I-like cells. Virology. 2008 Mar 1;372(1):127-35. doi: 10.1016/j.virol.2007.09.045. Epub 2007 Nov 26.
• Lesur O, Arsalane K, Lane D. Lung alveolar epithelial cell migration in vitro: modulators and regulation processes. Am J Physiol. 1996 Mar;270(3 Pt 1):L311-9. doi: 10.1152/ajplung.1996.270.3.L311.
• Berthiaume Y, Lesur O, Dagenais A. Treatment of adult respiratory distress syndrome: plea for rescue therapy of the alveolar epithelium. Thorax. 1999 Feb;54(2):150-60. doi: 10.1136/thx.54.2.150. No abstract available.
• Lesur O, Berthiaume Y, Blaise G, Damas P, Deland E, Guimond JG, Michel RP. Acute respiratory distress syndrome: 30 years later. Can Respir J. 1999 Jan-Feb;6(1):71-86. doi: 10.1155/1999/812476.
• Park J, Pabon M, Choi AMK, Siempos II, Fredenburgh LE, Baron RM, Jeon K, Chung CR, Yang JH, Park CM, Suh GY. Plasma surfactant protein-D as a diagnostic biomarker for acute respiratory distress syndrome: validation in US and Korean cohorts. BMC Pulm Med. 2017 Dec 15;17(1):204. doi: 10.1186/s12890-017-0532-1.
• Lesur O, Langevin S, Berthiaume Y, Legare M, Skrobik Y, Bellemare JF, Levy B, Fortier Y, Lauzier F, Bravo G, Nickmilder M, Rousseau E, Bernard A; Critical Care Research Group of the Quebec Respiratory Health Network. Outcome value of Clara cell protein in serum of patients with acute respiratory distress syndrome. Intensive Care Med. 2006 Aug;32(8):1167-74. doi: 10.1007/s00134-006-0235-1. Epub 2006 Jun 23.
• Lesur O, Hermans C, Chalifour JF, Picotte J, Levy B, Bernard A, Lane D. Mechanical ventilation-induced pneumoprotein CC-16 vascular transfer in rats: effect of KGF pretreatment. Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L410-9. doi: 10.1152/ajplung.00384.2001. Epub 2002 Oct 25.
• Wosten-van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, van Goor H, Kamilic J, Florquin S, Bos AP. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1-7) or an angiotensin II receptor antagonist. J Pathol. 2011 Dec;225(4):618-27. doi: 10.1002/path.2987. Epub 2011 Oct 18.
• Zhang R, Pan Y, Fanelli V, Wu S, Luo AA, Islam D, Han B, Mao P, Ghazarian M, Zeng W, Spieth PM, Wang D, Khang J, Mo H, Liu X, Uhlig S, Liu M, Laffey J, Slutsky AS, Li Y, Zhang H. Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway. Am J Respir Crit Care Med. 2015 Aug 1;192(3):315-23. doi: 10.1164/rccm.201412-2326OC.
• Marsault E, Llorens-Cortes C, Iturrioz X, Chun HJ, Lesur O, Oudit GY, Auger-Messier M. The apelinergic system: a perspective on challenges and opportunities in cardiovascular and metabolic disorders. Ann N Y Acad Sci. 2019 Nov;1455(1):12-33. doi: 10.1111/nyas.14123. Epub 2019 Jun 25.
• Coquerel D, Sainsily X, Dumont L, Sarret P, Marsault E, Auger-Messier M, Lesur O. The apelinergic system as an alternative to catecholamines in low-output septic shock. Crit Care. 2018 Jan 19;22(1):10. doi: 10.1186/s13054-018-1942-z.
• Raab WH, Magerl W, Muller H. Changes in dental blood flow following electrical tooth pulp stimulation--influences of capsaicin and guanethidine. Agents Actions. 1988 Dec;25(3-4):237-9. doi: 10.1007/BF01965022.
• Berta J, Kenessey I, Dobos J, Tovari J, Klepetko W, Jan Ankersmit H, Hegedus B, Renyi-Vamos F, Varga J, Lorincz Z, Paku S, Ostoros G, Rozsas A, Timar J, Dome B. Apelin expression in human non-small cell lung cancer: role in angiogenesis and prognosis. J Thorac Oncol. 2010 Aug;5(8):1120-9. doi: 10.1097/JTO.0b013e3181e2c1ff.
• Zhang H, Chen S, Zeng M, Lin D, Wang Y, Wen X, Xu C, Yang L, Fan X, Gong Y, Zhang H, Kong X. Apelin-13 Administration Protects Against LPS-Induced Acute Lung Injury by Inhibiting NF-kappaB Pathway and NLRP3 Inflammasome Activation. Cell Physiol Biochem. 2018;49(5):1918-1932. doi: 10.1159/000493653. Epub 2018 Sep 20.
• Visser YP, Walther FJ, Laghmani el H, Laarse Av, Wagenaar GT. Apelin attenuates hyperoxic lung and heart injury in neonatal rats. Am J Respir Crit Care Med. 2010 Nov 15;182(10):1239-50. doi: 10.1164/rccm.200909-1361OC. Epub 2010 Jul 9.
• Zhang L, Li F, Su X, Li Y, Wang Y, Fang R, Guo Y, Jin T, Shan H, Zhao X, Yang R, Shan H, Liang H. Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction. Exp Mol Med. 2019 Jul 4;51(7):1-12. doi: 10.1038/s12276-019-0273-8.
• He L, Xu J, Chen L, Li L. Apelin/APJ signaling in hypoxia-related diseases. Clin Chim Acta. 2015 Dec 7;451(Pt B):191-8. doi: 10.1016/j.cca.2015.09.029. Epub 2015 Oct 3.
• Andersen CU, Markvardsen LH, Hilberg O, Simonsen U. Pulmonary apelin levels and effects in rats with hypoxic pulmonary hypertension. Respir Med. 2009 Nov;103(11):1663-71. doi: 10.1016/j.rmed.2009.05.011. Epub 2009 Jun 17.
• Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, Llorens-Cortes C, Hazra S, Murray AG, Vederas JC, Oudit GY. Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System. Hypertension. 2016 Aug;68(2):365-77. doi: 10.1161/HYPERTENSIONAHA.115.06892. Epub 2016 May 23.
• Siddiquee K, Hampton J, McAnally D, May L, Smith L. The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. Br J Pharmacol. 2013 Mar;168(5):1104-17. doi: 10.1111/j.1476-5381.2012.02192.x.
• Zhou N, Zhang X, Fan X, Argyris E, Fang J, Acheampong E, DuBois GC, Pomerantz RJ. The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity. Virology. 2003 Dec 5;317(1):84-94. doi: 10.1016/j.virol.2003.08.026.
• Zou MX, Liu HY, Haraguchi Y, Soda Y, Tatemoto K, Hoshino H. Apelin peptides block the entry of human immunodeficiency virus (HIV). FEBS Lett. 2000 May 4;473(1):15-8. doi: 10.1016/s0014-5793(00)01487-3.
• Zhou N, Fang J, Mukhtar M, Acheampong E, Pomerantz RJ. Inhibition of HIV-1 fusion with small interfering RNAs targeting the chemokine coreceptor CXCR4. Gene Ther. 2004 Dec;11(23):1703-12. doi: 10.1038/sj.gt.3302339.
• Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008 May;93(5):543-8. doi: 10.1113/expphysiol.2007.040048. Epub 2008 Apr 10.
• Jia H. Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease. Shock. 2016 Sep;46(3):239-48. doi: 10.1097/SHK.0000000000000633.

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2020
• Primary Completion (Actual): October 1, 2021
• Study Completion (Actual): October 1, 2021

Study Registration Dates

• First Submitted: November 3, 2020
• First Submitted That Met QC Criteria: November 16, 2020
• First Posted (Actual): November 17, 2020

Study Record Updates

• Last Update Posted (Estimate): December 23, 2022
• Last Update Submitted That Met QC Criteria: December 21, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Covid19; ARDS; inflammation; SARS; ACE2; kallikrein-kinin; Apelins; ras; lung permeability biomarkers; ELABELA
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: 2021-3862-APEL-COVID

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No