The Mechanism of lncRNA NEAT1 in Alleviating Acute Respiratory Distress Syndrome Through miR-27b Regulated Nrf2 Pathway

NCT04937855 | Unknown

• 1 other identifier: 81970067
• Study Type: observational
• Target: 425
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Acute Respiratory Distress Syndrome; Inflammation

Keywords

long non-coding RNA NEAT1; microRNA-27b; nuclear factor E2-related factor 2

Outcome Measures

Primary Outcomes (10)

• The expression of lncRNA NEAT1 in blood and BALF in all groups

  Use RT-PCR to measure the expression of lncRNA NEAT1 in blood and BALF in all groups

  up to 24 day

• The expression of miR-27b in blood and BALF in all groups

  Use RT-PCR to measure the expression of miR-27b in blood and BALF in all groups

  up to 3 day

• The expression of Nrf2 in blood and BALF in all groups

  Use RT-PCR and Wsetern blot to measure the expression of Nrf2 in blood and BALF in all groups

  up to 3 day

• The expression of inflammatory factors(IL-1β、IL-6、IL-18、TNF-α) in blood and BALF in all groups

  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

  up to 3 day

• The expression of oxidative stress associated factors in blood and BALF in all groups

  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

• The numbers and kinds of inflammatory cells in BALF and blood in all groups

  Use flow cytometry to detect the number of inflammatory cells in BALF and blood in all groups

  up to 3 day

• The kinds of inflammatory cells in BALF and blood in all groups

  Use flow cytometry to detect the kinds of inflammatory cells(neutrophile、macrophage、 lymphocyte) in BALF and blood in all groups

  up to 3 day

• The time of mechanical ventilation of patients in ARDS groups

  Record the time of mechanical ventilation of patients in ARDS groups

  up to28 day

• The severity of ARDS patients in ARDS groups

  Record the severity(PaO2/FiO2、OI、S/F、OSI) of ARDS patients in ARDS groups

  up to 28 day

• the mortality in 28 days of ARDS patients

  Record the mortality in 28 days of ARDS patients

  up to 28 day

Secondary Outcomes (3)

• The differences and correlation of the expressions of lncRNA NEAT1、miR-27b and Nrf2 in the groups

  up to 28 day

• 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

  up to 28 day

Study Arms (5)

Control group

25 gender and age matching healthy controls

Other: no intervention

ARDS group 1

100 ARDS patients at the time of check in hospital

Other: no intervention

ARDS group 2

100 ARDS patients at the time of 24h after check in hospital

Other: no intervention

ARDS group 3

100 ARDS patients at the time of 48h after check in hospital

Other: no intervention

ARDS group 4

100 ARDS patients at the time of 72h after check in hospital

Other: no intervention

Interventions

no intervention OTHER

no intervention

ARDS group 1; ARDS group 2; ARDS group 3; ARDS group 4; Control group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

We included ARDS patients from RICU、EICU、SICU、CCU in Beijing Anzhen hospital between 2020 and 2022

You may qualify if:

• 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);
• \~70 years old;
• Agree to participate in the trial, and sign the informed consent.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Beijing Anzhen Hospital: lead

Study Sites (1)

Department of Respiratory and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases

Beijing, Beijing Municipality, 100029, China

Location

Related Publications (19)

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  PMID: 22797452 BACKGROUND

• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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Biospecimen

Retention: SAMPLES WITH DNA

Blood and BALF will be stored at -70˚C

MeSH Terms

Conditions

Respiratory Distress Syndrome; Inflammation

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Head of Respiratory and Critical Medicine Department

Study Record Dates

• First Submitted: January 11, 2020
• First Posted: June 24, 2021
• Study Start: July 1, 2021
• Primary Completion: December 31, 2022
• Study Completion: December 31, 2023
• Last Updated: June 24, 2021

Record last verified: 2021-06

Locations

CN (1)