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MiRNA-122 Promotes Ischemia-Reperfusion Injury after Lung Transplantation via the Toll-like Receptor Signaling Pathway

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Abstract

Objective

MiRNAs have been recently implicated in the pathogenesis of ischemia-reperfusion (IR) injury. This study aimed to investigate the miRNA expression profiles in the early stages after lung transplantation (LT) and to study the involvement of the Toll-like receptor (TLR) signaling pathway in lung IR injury following LT.

Methods

We established the left LT model in mice and selected the miRNA-122 as a research target. The mice were injected with a miRNA-122-specific inhibitor, following which pathological changes in the lung tissue were studied using different lung injury indicators. In addition, we performed deep sequencing of transplanted lung tissues to identify differentially expressed (DE) miRNAs and their target genes. These target genes were used to further perform gene ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.

Results

A total of 12 DE miRNAs were selected, and 2476 target genes were identified. The GO enrichment analysis predicted 6063 terms, and the KEGG analysis predicted 1554 biological pathways. Compared with the control group, inhibiting the expression of miRNA-122 significantly reduced the lung injury and lung wet/dry ratio (P<0.05). In addition, the activity of myeloperoxidase and the expression levels of tumor necrosis factor-alpha and TLR2/4 were decreased (P<0.05); whereas the expression of interleukin-10 was increased (P<0.05). Furthermore, the inhibition of miRNA-122 suppressed the IR injury-induced activation of the TLR signaling pathway.

Conclusion

Our findings showed the differential expression of several miRNAs in the early inflammatory response following LT. Of these, miRNA-122 promoted IR injury following LT, whereas its inhibition prevented IR injury in a TLR-dependent manner.

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References

  1. Simonson B, Das S. MicroRNA Therapeutics: the Next Magic Bullet? Mini Rev Med Chem, 2015,15(6):467–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rodriguez A, Griffiths-Jones S, Ashurst JL, et al. Identification of Mammalian microRNA Host Genes and Transcription Units. Genome Res, 2004,14(10a):1902–1910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhou L, Zang G, Zhang G, et al. MicroRNA and mRNA signatures in ischemia reperfusion injury in heart transplantation. PLoS One, 2013,8(11):e79805

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hu Y, Deng H, Xu S, et al. MicroRNAs Regulate Mitochondrial Function in Cerebral Ischemia-Reperfusion Injury. Int J Mol Sci, 2015,16(10):24895–24917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rancan L, Simon C, Marchal-Duval E, et al. Lidocaine Administration Controls MicroRNAs Alterations Observed After Lung Ischemia-Reperfusion Injury. Anesth Analg, 2016,123(6):1437–1447

    Article  CAS  PubMed  Google Scholar 

  6. Buermans HP, Ariyurek Y, Ommen G, et al. New methods for next generation sequencing based microRNA expression profiling. BMC Genomics, 2010,11:716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Campbell JD, Liu G, Luo L, et al. Assessment of microRNA differential expression and detection in multiplexed small RNA sequencing data. Rna, 2015, 21(2):164–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Siegel TN, Gunasekera K, Cross GAM, et al. Gene expression in Trypanosoma brucei: lessons from high-throughput RNA sequencing. Trends Parasitol, 2011, 27(10):434–441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Qin H, Sha J, Jiang C, et al. miR-122 inhibits metastasis and epithelial-mesenchymal transition of non-small-cell lung cancer cells. Onco Targets Ther, 2015,8:3175–3184

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shibata C, Ohno M, Otsuka M, et al. The flavonoid apigenin inhibits hepatitis C virus replication by decreasing mature microRNA122 levels. Virology, 2014,462–463:42–48

    Article  PubMed  Google Scholar 

  11. Xu M, Li D, Yang C, et al. MicroRNA-34a Inhibition of the TLR Signaling Pathway Via CXCL10 Suppresses Breast Cancer Cell Invasion and Migration. Cell Physiol Biochem, 2018,46(3):1286–1304

    Article  CAS  PubMed  Google Scholar 

  12. Nahid MA, Satoh M, Chan EK. MicroRNA in TLR signaling and endotoxin tolerance. Cell Mol Immunol, 2011,8(5):388–403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu HS, Zhang L, Chen Y, et al. Effect of nitric oxide on toll-like receptor 2 and 4 gene expression in rats with acute lung injury complicated by acute hemorrhage necrotizing pancreatitis. Hepatobiliary Pancreat Dis Int, 2005,4(4):609–613

    CAS  PubMed  Google Scholar 

  14. Jin X, Wang L, Wu HS, et al. N-acetylcysteine inhibits activation of toll-like receptor 2 and 4 gene expression in the liver and lung after partial hepatic ischemia-reperfusion injury in mice. Hepatobiliary Pancreat Dis Int, 2007,6(3):284–289

    CAS  PubMed  Google Scholar 

  15. Zheng Z, Wang J, Huang X, et al. Improvements of the surgical technique on the established mouse model of orthotopic single lung transplantation. PLoS One, 2013,8(11):e81000

    Article  PubMed  PubMed Central  Google Scholar 

  16. Smith KM, Mrozek JD, Simonton SC, et al. Prolonged partial liquid ventilation using conventional and high-frequency ventilatory techniques: gas exchange and lung pathology in an animal model of respiratory distress syndrome. Crit Care Med, 1997,25(11):1888–1897

    Article  CAS  PubMed  Google Scholar 

  17. Lin L, Li M, Lin L, et al. FPPS mediates TGF-beta1-induced non-small cell lung cancer cell invasion and the EMT process via the RhoA/Rock1 pathway. Biochem Biophys Res Commun, 2018,496(2):536–541

    Article  CAS  PubMed  Google Scholar 

  18. He Q, Zhao X, Bi S, et al. Pretreatment with Erythropoietin Attenuates Lung Ischemia/Reperfusion Injury via Toll-Like Receptor-4/Nuclear Factor-kappaB (TLR4/NF-kappaB) Pathway. Med Sci Monit, 2018,24:1251–1257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fanelli V, Costamagna A, Carosso F, et al. Effects of liver ischemia-reperfusion injury on respiratory mechanics and driving pressure during orthotopic liver transplantation. Minerva Anestesiol, 2019,85(5):494–504

    Article  PubMed  Google Scholar 

  20. Wang J, Cao H, Hong X, et al. MicroRNA screening and functional study of obliterative bronchiolitis in a rat model simulating lung transplantation. Genet Mol Res, 2015,14(4):19309–19316

    Article  CAS  PubMed  Google Scholar 

  21. Zheng Z, Chiu S, Akbarpour M, et al. Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction. Sci Transl Med, 2017,9(394):eaal4508

    Article  PubMed  PubMed Central  Google Scholar 

  22. Varga ZV, Zvara A, Farago N, et al. MicroRNAs associated with ischemia-reperfusion injury and cardioprotection by ischemic pre- and postconditioning: protectomiRs. Am J Physiol Heart Circ Physiol, 2014, 307(2):H216–227

    Article  CAS  PubMed  Google Scholar 

  23. Lorenzen JM, Kaucsar T, Schauerte C, et al. MicroRNA-24 antagonism prevents renal ischemia reperfusion injury. J Am Soc Nephrol, 2014,25(12):2717–2729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li P, Shen M, Gao F, et al. An Antagomir to MicroRNA-106b-5p Ameliorates Cerebral Ischemia and Reperfusion Injury in Rats Via Inhibiting Apoptosis and Oxidative Stress. Mol Neurobiol, 2017,54(4):2901–2921

    Article  CAS  PubMed  Google Scholar 

  25. Ma D, Jia H, Qin M, et al. MiR-122 Induces Radiosensitization in Non-Small Cell Lung Cancer Cell Line. Int J Mol Sci, 2015,16(9):22137–22150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gracia A, Quintela AF, Miranda J, et al. Are miRNA-103, miRNA-107 and miRNA-122 Involved in the Prevention of Liver Steatosis Induced by Resveratrol? Nutrients, 2017,9(4):360

    Article  PubMed Central  Google Scholar 

  27. Xu Z, Sharma M, Gelman A, et al. Significant role for microRNA-21 affecting toll-like receptor pathway in primary graft dysfunction after human lung transplantation. J Heart Lung Transplant, 2017,36(3): 331–339

    Article  PubMed  Google Scholar 

  28. Wang H, Zhang X, Zheng X, et al. Prevention of allograft rejection in heart transplantation through concurrent gene silencing of TLR and Kinase signaling pathways. Sci Rep, 2016,6:33869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sadis C, Detienne S, Vokear B, et al. The cholinergic anti-inflammatory pathway delays TLR-induced skin allograft rejection in mice: cholinergic pathway modulates alloreactivity. PLoS One, 2013,8(11):e79984

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zheng Z, Wang J, Hu H, et al. Short-term inhalation of nitric oxide inhibits activations of toll-like receptor 2 and 4 in the lung after ischemia-reperfusion injury in mice. J Huazhong Univ Sci Technolog Med Sci, 2013,33(2):219–223

    Article  CAS  PubMed  Google Scholar 

  31. Luo J, Zhan J, You H, et al. MicroRNA146a/Tolllike receptor 4 signaling protects against severe burninduced remote acute lung injury in rats via antiinflammation. Mol Med Rep, 2018,17(6):8377–8384

    CAS  PubMed  Google Scholar 

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Acknowledgments

First of all, I would like to express my sincere thanks to all those who have helped me in the course of my writing this paper. I would also like to take this opportunity to show my sincere gratitude to my supervisors, Zhi-kun ZHENG and Jin-song LI. They gave me many useful suggestions on my writing and tried their best to improve my thesis. Secondly, I would like to express my gratitude to my classmates who offered me references and information on time. Last but not the least, I would like to thank my teachers and their staff. Without their help, it would be much more difficult for me to finish my study and this paper.

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Author notes

  1. The authors contributed equally to this work.

Authors and Affiliations

  1. Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yuan Lu, Quan Liu, Peng Zhou, Pei-yuan Mei, Jin-song Li & Zhi-kun Zheng

  2. Department of Pediatric Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Ya-li Wang

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  1. Yuan Lu
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Correspondence to Jin-song Li or Zhi-kun Zheng.

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Conflict of Interest Statement

The authors declare that they have no conflicts of interest.

Author Jin-song LI is a member of the Editorial Board for Current Medical Science. The paper was handled by the other editor and has undergone rigorous peer review process. Author Jin-song LI was not involved in the journal’s review of, or decision related to, this manuscript.

This study was supported by grants from the National Natural Science Foundation of China (No. 81600074) and Hubei Natural Science Foundation (No. 2017CFB473).

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Lu, Y., Wang, Yl., Liu, Q. et al. MiRNA-122 Promotes Ischemia-Reperfusion Injury after Lung Transplantation via the Toll-like Receptor Signaling Pathway. CURR MED SCI 41, 1231–1238 (2021). https://doi.org/10.1007/s11596-021-2487-y

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  • DOI: https://doi.org/10.1007/s11596-021-2487-y

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