The Mechanism of lncRNA NEAT1 in Alleviating Acute Respiratory Distress Syndrome Through miR-27b Regulated Nrf2 Pathway
16 juni 2021 bijgewerkt door: Guangfa Zhu, Beijing Anzhen Hospital
The acute respiratory distress syndrome, formerly known as the acute lung injury (ARDS/ALI), is a critical illness with high mortality due to the lack of effective treatment.
The pathogenesis of ARDS/ALI has not been fully elucidated.
Nuclear factor E2-related factor 2 (Nrf2) plays a key role in regulating lung inflammation and oxidative stress which are closely related to lung injury in ARDS/ALI, but its regulatory mechanism remains unclear.
The investigator's provious study shown that microRNA-27b (miR-27b) downregulated Nrf2 to aggravate lung inflammation and histological injury.
Furthermore, in lipopolysaccharide (LPS)-induced cell (J774A.1)
inflammation model, miR-27b was upregulated while the long non-coding RNA (lncRNA) NEAT1 was downregulated, the putative binding sites of lncRNA NEAT1 and miR-27b were successfully predicted by bioinformatics approach.
Thus, the investigators propose that NEAT1 plays as a competing endogenous RNA (ceRNA) to adsorb miR-27b and liberate Nrf2, therefore, to attenuate lung inflammation and related lung injury in ARDS/ALI.
This project aims to explore the role of the lncRNA NEAT1/ mir-27b /Nrf2 signal axis in the development and treatment of ARDS/ALI in patients, as well as in LPS-induced ALI animal and cell models by using bioinformatics, molecular biology, histomorphology and clinical phenotype approaches, and to clarify the new mechanism in ARDS/ALI development and to provide new therapeutic targets.
Studie Overzicht
Toestand
Aanmelden op uitnodiging
Interventie / Behandeling
Gedetailleerde beschrijving
Collect blood and BALF from 400 ARDS patients at different time (at check-in, 24, 48 and 72 h after check-in the hospital) and 25 gender and age matching healthy controls.
Use RT-PCR to detect the expression of lncRNA NEAT1、miR-27b and Nrf2 in blood and BALF of ARDS patients and health controls.
The expressions of inflammatory and oxidative stress associated factors (NLRP3、NF-κB-P65、 p-P65、IκB、p-IκB、HO-1、NQO1、caspase-1、IL-1β、IL-6、IL-18、TNF-α) will be detected by western blot、ELISA and RT-PCR.
Moreover, flow cytometry will be adopted to measure the numbers and kinds of cells in BALF.
Then, analyze the differences of the expressions of lncRNA NEAT1、miR-27b and Nrf2 in the groups.
To explore the correlation of expressions of lncRNA NEAT1、miR-27b and Nrf2 with inflammation and oxidative stress in the groups.
Finally, to declare the relative of lncRNA NEAT1、miR-27b and Nrf2 with the time of mechanical ventilation, severity and mortality in 28 days of ARDS patients.
Studietype
Observationeel
Inschrijving (Verwacht)
425
Contacten en locaties
In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.
Studie Locaties
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Beijing
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Beijing, Beijing, China, 100029
- Department of Respiratory and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases
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Deelname Criteria
Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.
Geschiktheidscriteria
Leeftijden die in aanmerking komen voor studie
18 jaar tot 70 jaar (Volwassen, Oudere volwassene)
Accepteert gezonde vrijwilligers
Ja
Geslachten die in aanmerking komen voor studie
Allemaal
Bemonsteringsmethode
Kanssteekproef
Studie Bevolking
We included ARDS patients from RICU、EICU、SICU、CCU in Beijing Anzhen hospital between 2020 and 2022
Beschrijving
Inclusion Criteria:
We included patients with acute respiratory distress according to 2012 ARDS Berlin new definition (Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA, 2012, 307(23):2526).
- Acute or progressive dyspnea within 1 week with identify cause;
- Chest radiograph/chest CT showed double lung infiltration, which could not be fully explained by pleural effusion, atelectasis, or nodules;
- Respiratory failure cannot be fully explained by heart failure and fluid overload;
- Hypoxemia, partial pressure of oxygen in arterial blood (PaO2)/oxygen fraction in air (FIO2) <150 mm Hg under PEEP ≥5 cm H2O, (mild ARDS: 200mmHg<PaO2/FiO2≤300mmHg, moderate ARDS: 100mmHg<PaO2/FiO2≤200mmHg, severe ARDS: PaO2/FiO2≤100mmHg);
- 18~70 years old;
- Agree to participate in the trial, and sign the informed consent.
Exclusion Criteria:
- Age less than 18 years old;
- Time of hospital stay <24 h;
- Pregnancy;
- Using V-V ECOM;
- Cardiac index <1.5L·ml.min-1.m-2;
- Pulmonary resection;
- Pulmonary embolism ;
- Refused to participate in the study.
Studie plan
Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.
Hoe is de studie opgezet?
Ontwerpdetails
Cohorten en interventies
Groep / Cohort |
Interventie / Behandeling |
|---|---|
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Control group
25 gender and age matching healthy controls
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geen tussenkomst
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ARDS group 1
100 ARDS patients at the time of check in hospital
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geen tussenkomst
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ARDS group 2
100 ARDS patients at the time of 24h after check in hospital
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geen tussenkomst
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ARDS group 3
100 ARDS patients at the time of 48h after check in hospital
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geen tussenkomst
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ARDS group 4
100 ARDS patients at the time of 72h after check in hospital
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geen tussenkomst
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Wat meet het onderzoek?
Primaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
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The expression of lncRNA NEAT1 in blood and BALF in all groups
Tijdsspanne: up to 24 day
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Use RT-PCR to measure the expression of lncRNA NEAT1 in blood and BALF in all groups
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up to 24 day
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The expression of miR-27b in blood and BALF in all groups
Tijdsspanne: up to 3 day
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Use RT-PCR to measure the expression of miR-27b in blood and BALF in all groups
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up to 3 day
|
|
The expression of Nrf2 in blood and BALF in all groups
Tijdsspanne: up to 3 day
|
Use RT-PCR and Wsetern blot to measure the expression of Nrf2 in blood and BALF in all groups
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up to 3 day
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The expression of inflammatory factors(IL-1β、IL-6、IL-18、TNF-α) in blood and BALF in all groups
Tijdsspanne: up to 3 day
|
Use RT-PCR and ELISA to measure the expression of inflammatory factors(IL-1β、IL-6、IL-18、TNF-α) in blood and BALF in all groups
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up to 3 day
|
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The expression of oxidative stress associated factors in blood and BALF in all groups
Tijdsspanne: up to 3 day
|
Use Western blot to measure the expression of oxidative stress associated factors(NLRP3、NF-κB-P65、 p-P65、IκB、p-IκB、HO-1、NQO1、caspase-1) in blood and BALF in all groups
|
up to 3 day
|
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The numbers and kinds of inflammatory cells in BALF and blood in all groups
Tijdsspanne: up to 3 day
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Use flow cytometry to detect the number of inflammatory cells in BALF and blood in all groups
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up to 3 day
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The kinds of inflammatory cells in BALF and blood in all groups
Tijdsspanne: up to 3 day
|
Use flow cytometry to detect the kinds of inflammatory cells(neutrophile、macrophage、 lymphocyte) in BALF and blood in all groups
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up to 3 day
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The time of mechanical ventilation of patients in ARDS groups
Tijdsspanne: up to28 day
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Record the time of mechanical ventilation of patients in ARDS groups
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up to28 day
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The severity of ARDS patients in ARDS groups
Tijdsspanne: up to 28 day
|
Record the severity(PaO2/FiO2、OI、S/F、OSI) of ARDS patients in ARDS groups
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up to 28 day
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the mortality in 28 days of ARDS patients
Tijdsspanne: up to 28 day
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Record the mortality in 28 days of ARDS patients
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up to 28 day
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Secundaire uitkomstmaten
Uitkomstmaat |
Maatregel Beschrijving |
Tijdsspanne |
|---|---|---|
|
The differences and correlation of the expressions of lncRNA NEAT1、miR-27b and Nrf2 in the groups
Tijdsspanne: up to 28 day
|
Analyse the differences of the expressions of lncRNA NEAT1、miR-27b and Nrf2 in the groups, and to explore the relations between the three(lncRNA NEAT1、miR-27b and Nrf2) in different groups.
|
up to 28 day
|
|
The correlation of expressions of lncRNA NEAT1、miR-27b and Nrf2 with inflammation and oxidative stress in the groups.
Tijdsspanne: up to 28 day
|
To explore the correlation of expressions of lncRNA NEAT1、miR-27b and Nrf2 with inflammation and oxidative stress in the groups.
|
up to 28 day
|
|
The relative of lncRNA NEAT1、miR-27b and Nrf2 with the time of mechanical ventilation, severity and mortality in 28 days of ARDS patients
Tijdsspanne: up to 28 day
|
To declare the relative of lncRNA NEAT1、miR-27b and Nrf2 with the time of mechanical ventilation, severity and mortality in 28 days of ARDS patients
|
up to 28 day
|
Medewerkers en onderzoekers
Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.
Sponsor
Publicaties en nuttige links
De persoon die verantwoordelijk is voor het invoeren van informatie over het onderzoek stelt deze publicaties vrijwillig ter beschikking. Dit kan gaan over alles wat met het onderzoek te maken heeft.
Algemene publicaties
- Fan E, Brodie D, Slutsky AS. Acute Respiratory Distress Syndrome: Advances in Diagnosis and Treatment. JAMA. 2018 Feb 20;319(7):698-710. doi: 10.1001/jama.2017.21907.
- Signorelli SS, Volsi GL, Pitruzzella A, Fiore V, Mangiafico M, Vanella L, Parenti R, Rizzo M, Volti GL. Circulating miR-130a, miR-27b, and miR-210 in Patients With Peripheral Artery Disease and Their Potential Relationship With Oxidative Stress. Angiology. 2016 Nov;67(10):945-950. doi: 10.1177/0003319716638242. Epub 2016 Jul 11.
- Liu Q, Lv H, Wen Z, Ci X, Peng L. Isoliquiritigenin Activates Nuclear Factor Erythroid-2 Related Factor 2 to Suppress the NOD-Like Receptor Protein 3 Inflammasome and Inhibits the NF-kappaB Pathway in Macrophages and in Acute Lung Injury. Front Immunol. 2017 Nov 9;8:1518. doi: 10.3389/fimmu.2017.01518. eCollection 2017.
- 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.
- Lu MC, Ji JA, Jiang ZY, You QD. The Keap1-Nrf2-ARE Pathway As a Potential Preventive and Therapeutic Target: An Update. Med Res Rev. 2016 Sep;36(5):924-63. doi: 10.1002/med.21396. Epub 2016 May 18.
- Wei J, Chen G, Shi X, Zhou H, Liu M, Chen Y, Feng D, Zhang P, Wu L, Lv X. Nrf2 activation protects against intratracheal LPS induced mouse/murine acute respiratory distress syndrome by regulating macrophage polarization. Biochem Biophys Res Commun. 2018 Jun 7;500(3):790-796. doi: 10.1016/j.bbrc.2018.04.161. Epub 2018 Apr 25.
- Liu Y, Song M, Zhu G, Xi X, Li K, Wu C, Huang L. Corynoline attenuates LPS-induced acute lung injury in mice by activating Nrf2. Int Immunopharmacol. 2017 Jul;48:96-101. doi: 10.1016/j.intimp.2017.04.029. Epub 2017 May 6.
- Rajasekaran S, Pattarayan D, Rajaguru P, Sudhakar Gandhi PS, Thimmulappa RK. MicroRNA Regulation of Acute Lung Injury and Acute Respiratory Distress Syndrome. J Cell Physiol. 2016 Oct;231(10):2097-106. doi: 10.1002/jcp.25316. Epub 2016 Feb 4.
- Wu CT, Huang Y, Pei ZY, Xi X, Zhu GF. MicroRNA-326 aggravates acute lung injury in septic shock by mediating the NF-kappaB signaling pathway. Int J Biochem Cell Biol. 2018 Aug;101:1-11. doi: 10.1016/j.biocel.2018.04.019. Epub 2018 May 1.
- Ling Y, Li ZZ, Zhang JF, Zheng XW, Lei ZQ, Chen RY, Feng JH. MicroRNA-494 inhibition alleviates acute lung injury through Nrf2 signaling pathway via NQO1 in sepsis-associated acute respiratory distress syndrome. Life Sci. 2018 Oct 1;210:1-8. doi: 10.1016/j.lfs.2018.08.037. Epub 2018 Aug 17.
- Ding L, Ni J, Yang F, Huang L, Deng H, Wu Y, Ding X, Tang J. Promising therapeutic role of miR-27b in tumor. Tumour Biol. 2017 Mar;39(3):1010428317691657. doi: 10.1177/1010428317691657.
- Zhou R, Gong AY, Eischeid AN, Chen XM. miR-27b targets KSRP to coordinate TLR4-mediated epithelial defense against Cryptosporidium parvum infection. PLoS Pathog. 2012;8(5):e1002702. doi: 10.1371/journal.ppat.1002702. Epub 2012 May 17.
- Li T, Cao H, Zhuang J, Wan J, Guan M, Yu B, Li X, Zhang W. Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans. Clin Chim Acta. 2011 Jan 14;412(1-2):66-70. doi: 10.1016/j.cca.2010.09.029. Epub 2010 Sep 29.
- Huang Y, Huang L, Zhu G, Pei Z, Zhang W. Downregulated microRNA-27b attenuates lipopolysaccharide-induced acute lung injury via activation of NF-E2-related factor 2 and inhibition of nuclear factor kappaB signaling pathway. J Cell Physiol. 2019 May;234(5):6023-6032. doi: 10.1002/jcp.27187. Epub 2018 Dec 24.
- Song YX, Sun JX, Zhao JH, Yang YC, Shi JX, Wu ZH, Chen XW, Gao P, Miao ZF, Wang ZN. Non-coding RNAs participate in the regulatory network of CLDN4 via ceRNA mediated miRNA evasion. Nat Commun. 2017 Aug 18;8(1):289. doi: 10.1038/s41467-017-00304-1. Erratum In: Nat Commun. 2021 May 19;12(1):3149.
- Yan B, Yao J, Liu JY, Li XM, Wang XQ, Li YJ, Tao ZF, Song YC, Chen Q, Jiang Q. lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res. 2015 Mar 27;116(7):1143-56. doi: 10.1161/CIRCRESAHA.116.305510. Epub 2015 Jan 13.
- Wang Y, Xu Z, Jiang J, Xu C, Kang J, Xiao L, Wu M, Xiong J, Guo X, Liu H. Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. Dev Cell. 2013 Apr 15;25(1):69-80. doi: 10.1016/j.devcel.2013.03.002. Epub 2013 Mar 28.
- Xiong DD, Li ZY, Liang L, He RQ, Ma FC, Luo DZ, Hu XH, Chen G. The LncRNA NEAT1 Accelerates Lung Adenocarcinoma Deterioration and Binds to Mir-193a-3p as a Competitive Endogenous RNA. Cell Physiol Biochem. 2018;48(3):905-918. doi: 10.1159/000491958. Epub 2018 Jul 23. Erratum In: Cell Physiol Biochem. 2020;54(3):508-509.
- Wang L, Xia JW, Ke ZP, Zhang BH. Blockade of NEAT1 represses inflammation response and lipid uptake via modulating miR-342-3p in human macrophages THP-1 cells. J Cell Physiol. 2019 Apr;234(4):5319-5326. doi: 10.1002/jcp.27340. Epub 2018 Sep 27.
Studie record data
Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.
Bestudeer belangrijke data
Studie start (Verwacht)
1 juli 2021
Primaire voltooiing (Verwacht)
31 december 2022
Studie voltooiing (Verwacht)
31 december 2023
Studieregistratiedata
Eerst ingediend
11 januari 2020
Eerst ingediend dat voldeed aan de QC-criteria
16 juni 2021
Eerst geplaatst (Werkelijk)
24 juni 2021
Updates van studierecords
Laatste update geplaatst (Werkelijk)
24 juni 2021
Laatste update ingediend die voldeed aan QC-criteria
16 juni 2021
Laatst geverifieerd
1 juni 2021
Meer informatie
Termen gerelateerd aan deze studie
Aanvullende relevante MeSH-voorwaarden
Andere studie-ID-nummers
- 81970067
Informatie over medicijnen en apparaten, studiedocumenten
Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel
Nee
Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct
Nee
Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .