Download PDF
Am J Perinatol 2022; 39(10): 1089-1096
DOI: 10.1055/s-0040-1721498
Original Article

Mechanism of lncRNA H19 in Regulating Pulmonary Injury in Hyperoxia-Induced Bronchopulmonary Dysplasia Newborn Mice

Lina Zhang‡   *
1   Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
,
Ping Wang‡   *
2   Department of Hand and Foot Surgery, Nanchang Fifth Hospital, Nanchang, Jiangxi, People's Republic of China
,
Yanhong Shen
1   Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
,
Tao Huang
1   Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
,
Xiaoyun Hu
1   Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
,
Wei Yu
1   Department of Pediatrics, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China
› Author Affiliations Funding This study was supported by Science and Technology Plan of Jiangxi Health Department (no. 20195130).
› Further Information
Also available at
    Permissions and Reprints

Abstract

Objective Bronchopulmonary dysplasia (BPD) is a pulmonary injury related to inflammation and is a major cause of premature infant death. Long noncoding RNAs (lncRNAs) are important regulators in pulmonary injury and inflammation. We investigated the molecular mechanism of lncRNA H19 in pulmonary injury and inflammation in hyperoxia (Hyp)-induced BPD mice.

Study Design The BPD newborn mouse model was established and intervened with H19 to evaluate the pathologic conditions and radial alveolar count (RAC) in lung tissues of mice in the room air (RA) and Hyp group on the 4th, 7th, and 14th days after birth. The levels of BPD-related biomarkers vascular endothelial growth factor (VEGF), transforming growth factor β1 (TGF-β1), and surfactant protein C (SPC) in lung tissues were detected on the 14th day after birth. The expression of and relationships among H19 and miR-17, miR-17, and STAT3 were detected and verified. Levels of interleukin (IL)-6, IL-1β, p-STAT3, and STAT3 levels in mouse lung tissues were detected on the 14th day after birth.

Results Hyp-induced mice showed increased alveolar diameter, septum, and hyperemia and inflammatory cell infiltration, upregulated H19, decreased overall number and significantly reduced RAC on the 7th and 14th days after birth, which were reversed in the si-H19-treated mice. VEGF was upregulated and TGF-β1 and SPC was decreased in si-H19-treated mice. Moreover, H19 competitively bound to miR-17 to upregulate STAT3. IL-6 and IL-1β expressions and p-STAT3 and STAT3 levels were downregulated after inhibition of H19.

Conclusion Downregulated lncRNA H19 relieved pulmonary injury via targeting miR-17 to downregulate STAT3 and reduced inflammatory response caused by p-STAT3 in BPD newborn mice.

Key Points

  • lncRNA H19 was highly expressed in Hyp-induced BPD newborn mice.

  • si-H19 relieved pulmonary injury in Hyp-induced BPD newborn mice.

  • si-H19 upregulated miR-17 and downregulated STAT3 expression.

Keywords

bronchopulmonary dysplasia - lncRNA H19 - miR-17 - STAT3 - pulmonary injury - inflammatory response

* These authors contributed equally to this work.




Publication History

Received: 03 July 2020

Accepted: 02 November 2020

Article published online:
07 December 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Jobe AH. Mechanisms of lung injury and bronchopulmonary dysplasia. Am J Perinatol 2016; 33 (11) 1076-1078
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Principi N, Di Pietro GM, Esposito S. Bronchopulmonary dysplasia: clinical aspects and preventive and therapeutic strategies. J Transl Med 2018; 16 (01) 36
    CrossrefPubMedSearch in Google Scholar
  • 3 Chen X, Walther FJ, Sengers RM. et al. Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response. Am J Physiol Lung Cell Mol Physiol 2015; 309 (03) L262-L270
    CrossrefPubMedSearch in Google Scholar
  • 4 Wang L, Ma L, Xu F. et al. Role of long non-coding RNA in drug resistance in non-small cell lung cancer. Thorac Cancer 2018; 9 (07) 761-768
    CrossrefPubMedSearch in Google Scholar
  • 5 Bao TP, Wu R, Cheng HP, Cui XW, Tian ZF. Differential expression of long non-coding RNAs in hyperoxia-induced bronchopulmonary dysplasia. Cell Biochem Funct 2016; 34 (05) 299-309
    CrossrefPubMedSearch in Google Scholar
  • 6 Lal CV, Bhandari V, Ambalavanan N. Genomics, microbiomics, proteomics, and metabolomics in bronchopulmonary dysplasia. Semin Perinatol 2018; 42 (07) 425-431
    CrossrefPubMedSearch in Google Scholar
  • 7 Cai C, Qiu J, Qiu G. et al. Long non-coding RNA MALAT1 protects preterm infants with bronchopulmonary dysplasia by inhibiting cell apoptosis. BMC Pulm Med 2017; 17 (01) 199
    CrossrefPubMedSearch in Google Scholar
  • 8 Jiang X, Ning Q. The mechanism of lncRNA H19 in fibrosis and its potential as novel therapeutic target. Mech Ageing Dev 2020; 188: 111243
    CrossrefPubMedSearch in Google Scholar
  • 9 Ren J, Fu J, Ma T. et al. LncRNA H19-elevated LIN28B promotes lung cancer progression through sequestering miR-196b. Cell Cycle 2018; 17 (11) 1372-1380
    CrossrefPubMedSearch in Google Scholar
  • 10 Mo W, Li Y, Chang W, Luo Y, Mai B, Zhou J. The Role of LncRNA H19 in MAPK Signaling Pathway Implicated in the Progression of Bronchopulmonary Dysplasia. Cell Transplant 2020; 29: 963689720918294
    CrossrefPubMedSearch in Google Scholar
  • 11 Chen K, Ma Y, Wu S. et al. Construction and analysis of a lncRNA-miRNA-mRNA network based on competitive endogenous RNA reveals functional lncRNAs in diabetic cardiomyopathy. Mol Med Rep 2019; 20 (02) 1393-1403
    PubMedSearch in Google Scholar
  • 12 Huang Z, Lei W, Hu HB, Zhang H, Zhu Y. H19 promotes non-small-cell lung cancer (NSCLC) development through STAT3 signaling via sponging miR-17. J Cell Physiol 2018; 233 (10) 6768-6776
    CrossrefPubMedSearch in Google Scholar
  • 13 Robbins ME, Dakhlallah D, Marsh CB, Rogers LK, Tipple TE. Of mice and men: correlations between microRNA-17∼92 cluster expression and promoter methylation in severe bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2016; 311 (05) L981-L984
    CrossrefPubMedSearch in Google Scholar
  • 14 Menon RT, Shrestha AK, Shivanna B. Hyperoxia exposure disrupts adrenomedullin signaling in newborn mice: Implications for lung development in premature infants. Biochem Biophys Res Commun 2017; 487 (03) 666-671
    CrossrefPubMedSearch in Google Scholar
  • 15 Wu S, Tang S, Peng H. et al. Effects of lentivirus-mediated CCR3 RNA interference on the function of mast cells of allergic rhinitis in mice. Int Immunopharmacol 2020; 78: 106011
    CrossrefPubMedSearch in Google Scholar
  • 16 Hallman M, Haataja R. Surfactant protein polymorphisms and neonatal lung disease. Semin Perinatol 2006; 30 (06) 350-361
    CrossrefPubMedSearch in Google Scholar
  • 17 Lal CV, Ambalavanan N. Biomarkers, early diagnosis, and clinical predictors of bronchopulmonary dysplasia. Clin Perinatol 2015; 42 (04) 739-754
    CrossrefPubMedSearch in Google Scholar
  • 18 Wu QY, Cheng Z, Zhou YZ. et al. A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy. Cell Death Dis 2020; 11 (02) 131
    CrossrefPubMedSearch in Google Scholar
  • 19 Rutkowska M, Hożejowski R, Helwich E, Borszewska-Kornacka MK, Gadzinowski J. Severe bronchopulmonary dysplasia - incidence and predictive factors in a prospective, multicenter study in very preterm infants with respiratory distress syndrome. J Matern Fetal Neonatal Med 2019; 32 (12) 1958-1964
    CrossrefPubMedSearch in Google Scholar
  • 20 Liu X, Gao S, Xu H. lncRNAPCAT29 inhibits pulmonary fibrosis via the TGF‑β1‑regulated RASAL1/ERK1/2 signal pathway. Mol Med Rep 2018; 17 (06) 7781-7788
    PubMedSearch in Google Scholar
  • 21 Alam MA, Betal SGN, Aghai ZH, Bhandari V. Hyperoxia causes miR199a-5p-mediated injury in the developing lung. Pediatr Res 2019; 86 (05) 579-588
    CrossrefPubMedSearch in Google Scholar
  • 22 Yin LL, Ye ZZ, Tang LJ, Guo L, Huang WM. [Effect of rhubarb on neonatal rats with bronchopulmonary dysplasia induced by hyperoxia] (in Chinese). Zhongguo Dang Dai Er Ke Za Zhi 2018; 20 (05) 410-415
    PubMedSearch in Google Scholar
  • 23 Willis GR, Fernandez-Gonzalez A, Anastas J. et al. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am J Respir Crit Care Med 2018; 197 (01) 104-116
    CrossrefPubMedSearch in Google Scholar
  • 24 Willems S, Verleden SE, Vanaudenaerde BM. et al. Multiplex protein profiling of bronchoalveolar lavage in idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. Ann Thorac Med 2013; 8 (01) 38-45
    CrossrefPubMedSearch in Google Scholar
  • 25 Cai Y, Dong ZY, Wang JY. LncRNA NNT-AS1 is a major mediator of cisplatin chemoresistance in non-small cell lung cancer through MAPK/Slug pathway. Eur Rev Med Pharmacol Sci 2018; 22 (15) 4879-4887
    PubMedSearch in Google Scholar
  • 26 Lu Q, Guo Z, Xie W. et al. The lncRNA H19 mediates pulmonary fibrosis by regulating the miR-196a/COL1A1 axis. Inflammation 2018; 41 (03) 896-903
    CrossrefPubMedSearch in Google Scholar
  • 27 Yang W, Li X, Qi S. et al. lncRNA H19 is involved in TGF-β1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT Signaling Pathway. PeerJ 2017; 5: e3950
    CrossrefPubMedSearch in Google Scholar
  • 28 Johar D, Siragam V, Mahood TH, Keijzer R. New insights into lung development and diseases: the role of microRNAs. Biochem Cell Biol 2015; 93 (02) 139-148
    CrossrefPubMedSearch in Google Scholar
  • 29 Wang J, Yin J, Wang X. et al. Changing expression profiles of mRNA, lncRNA, circRNA, and miRNA in lung tissue reveal the pathophysiological of bronchopulmonary dysplasia (BPD) in mouse model. J Cell Biochem 2019; 120 (06) 9369-9380
    CrossrefPubMedSearch in Google Scholar
  • 30 Xie H, Xue JD, Chao F, Jin YF, Fu Q. Long non-coding RNA-H19 antagonism protects against renal fibrosis. Oncotarget 2016; 7 (32) 51473-51481
    CrossrefPubMedSearch in Google Scholar
  • 31 Carraro G, El-Hashash A, Guidolin D. et al. miR-17 family of microRNAs controls FGF10-mediated embryonic lung epithelial branching morphogenesis through MAPK14 and STAT3 regulation of E-Cadherin distribution. Dev Biol 2009; 333 (02) 238-250
    CrossrefPubMedSearch in Google Scholar
  • 32 Will JP, Hirani D, Thielen F. et al. Strain-dependent effects on lung structure, matrix remodeling, and Stat3/Smad2 signaling in C57BL/6N and C57BL/6J mice after neonatal hyperoxia. Am J Physiol Regul Integr Comp Physiol 2019; 317 (01) R169-R181
    CrossrefPubMedSearch in Google Scholar
  • 33 Liu L, Liu L, Lu S. lncRNA H19 promotes viability and epithelial-mesenchymal transition of lung adenocarcinoma cells by targeting miR-29b-3p and modifying STAT3. Int J Oncol 2019; 54 (03) 929-941
    PubMedSearch in Google Scholar
  • 34 Chen X, Zhang X, Pan J. Effect of montelukast on bronchopulmonary dysplasia (BPD) and related mechanisms. Med Sci Monit 2019; 25: 1886-1893
    CrossrefPubMedSearch in Google Scholar
  • 35 Tong M, Wang J, Jiang N, Pan H, Li D. Correlation between p-STAT3 overexpression and prognosis in lung cancer: a systematic review and meta-analysis. PLoS One 2017; 12 (08) e0182282
    CrossrefPubMedSearch in Google Scholar
  • 36 Hung YH, Hsieh WY, Hsieh JS. et al. Alternative roles of STAT3 and MAPK signaling pathways in the MMPs activation and progression of lung injury induced by cigarette smoke exposure in ACE2 knockout mice. Int J Biol Sci 2016; 12 (04) 454-465
    CrossrefPubMedSearch in Google Scholar