Abstract
Purpose
Ventilator-induced lung injury (VILI) is an additional inflammatory injury caused by mechanical ventilation (MV). This study aimed to determine the effects of microRNA-214 (miR-214) on VILI and its underlying mechanism of action.
Methods
To develop a VILI mouse model, mice were subjected to MV. The expression of miR-214 was detected by qRT-PCR. The macrophages, fibroblasts, epithelial cells, and endothelial cells were isolated from lung tissues by fluorescence-activated cell sorting. The histopathological changes of lung, lung wet/dry weight (W/D) ratio, and myeloperoxidase (MPO) activity were used to evaluate the degree of lung injury. The levels of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). Dual-luciferase reporter assay was performed to determine the interactions between miR-214 and FGFR1. Western blot was used to detect the protein expression of FGFR1, p-AKT, and p-PI3K.
Results
The expression of miR-214 was increased in lung tissues and macrophages, fibroblasts, epithelial cells, and endothelial cells isolated from lung tissues in VILI mice. MiR-214 inhibition decreased the histopathological changes of lung, lung W/D ratio, MPO activity, and pro-inflammatory cytokines levels in BALF in VILI mice. FGFR1 was targeted by miR-214. The protein expression of FGFR1 was decreased in VILI mice. Ponatinib (FGFR1 inhibitor) reversed the suppressive effects of miR-214 inhibition on lung injury and inflammation of VILI mice. MiR-214 increased the activity of PI3K/AKT pathway by regulating FGFR1.
Conclusions
Inhibition of miR-214 attenuated lung injury and inflammation in VILI mice by increasing FGFR1 expression, providing a novel therapeutic target for VILI.
Similar content being viewed by others
Data Availability
All data in the manuscript is available through the responsible corresponding author.
References
Curley GF, Laffey JG, Zhang H, Slutsky AS (2016) Biotrauma and ventilator-induced lung injury: clinical implications. Chest 150:1109–1117
Beitler JR, Malhotra A, Thompson BT (2016) Ventilator-induced Lung Injury. Clin Chest Med 37:633–646
Slutsky AS (2015) History of mechanical ventilation. from vesalius to ventilator-induced lung injury. Am J Respir Crit Care Med 191:1106–1115
Mahmoodpoor A, Golzari SE (2014) APRV mode in ventilator induced lung injury (VILI). Advances in Bioscience and Clinical Medicine 2:1–2
Cressoni M, Gotti M, Chiurazzi C et al (2016) Mechanical power and development of ventilator-induced lung injury. Anesthesiology 124:1100–1108
Kuipers MT, van der Poll T, Schultz MJ, Wieland CW (2011) Bench-to-bedside review: damage-associated molecular patterns in the onset of ventilator-induced lung injury. Crit Care 15:235
Li W, Qiu X, Jiang H, Han Y, Wei D, Liu J (2016) Downregulation of miR-181a protects mice from LPS-induced acute lung injury by targeting Bcl-2. Biomed Pharmacother 84:1375–1382
Lu W, You R, Yuan X et al (2015) The microRNA miR-22 inhibits the histone deacetylase HDAC4 to promote TH17 cell-dependent emphysema. Nat Immunol 16:1185–1194
Dakhlallah D, Batte K, Wang Y et al (2013) Epigenetic regulation of miR-17∼92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 187:397–405
Li QL, Ge YL, Li M et al (2017) miR-127 contributes to ventilator-induced lung injury. Mol Med Rep 16:4119–4126
Vaporidi K, Vergadi E, Kaniaris E et al (2012) Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury. Am J Physiol-Lung Cell Mol Physiol 303:199–207
Liu HT, Tao Y, Chen M et al (2016) Upregulation of MicroRNA-214 contributes to the development of vascular remodeling in hypoxia-induced pulmonary hypertension via targeting CCNL2. Scientific Reports 6:24661
Oka S, Furukawa H, Shimada K et al (2017) Plasma miRNA expression profiles in rheumatoid arthritis associated interstitial lung disease. BMC Musculoskelet Disord 18:21
Savary G, Buscot M, Dewaeles E et al (2014) MiR-214-3p, a new fibromiR involved in the pathogenesis of idiopathic pulmonary fibrosis. Eur Respir J 44:1731
Yuan T, Klinkhammer K, Lyu H et al (2020) Temporospatial expression of Fgfr1 and 2 during lung development, homeostasis, and regeneration. Front Pharmacol. 11:120
Chen P, Tang H, Zhang Q et al (2020) Basic fibroblast growth factor (bFGF) protects the blood-brain barrier by binding of FGFR1 and activating the ERK signaling pathway after intra-abdominal hypertension and traumatic brain injury. Med Sci Monit 26:e922009
Eash J, Olsen A, Breur GJ, Gerrard D, Hannon K (2007) FGFR1 inhibits skeletal muscle atrophy associated with hindlimb suspension. BMC Musculoskelet Disord 8:32–32
Yang Y, Haeger SM, Suflita MA et al (2017) Fibroblast growth factor signaling mediates pulmonary endothelial glycocalyx reconstitution. Am J Respir Cell Mol Biol 56:727–737
Ma S, Grigoryev DN, Easley RB, Ye SQ, Simon BA, Garcia JGN (2006) 33 Bioinformatic class discovery of potential biomarkers in ventilator-associated lung injury. J Invest Med 54:80
Wang Y, Xu CF, Liu YJ et al (2017) Salidroside attenuates ventilation induced lung injury via SIRT1-dependent inhibition of NLRP3 inflammasome. Cell Physiol Biochem 42:34–43
Yan X, Li W, Yang L et al (2018) MiR-135a protects vascular endothelial cells against ventilator-induced lung injury by inhibiting PHLPP2 to ACTIVATE PI3K/Akt pathway. Cell Physiol Biochem 48:1245–1258
Xu B, Wang Y, Li X, Mao Y, Deng X (2018) RNA-sequencing analysis of aberrantly expressed long non-coding RNAs and mRNAs in a mouse model of ventilator-induced lung injury. Mol Med Rep 18:882–892
Cagle LA, Franzi LM, Linderholm AL, Adams JY, Harper RW, Kenyon NJ (2017) Effects of positive end-expiratory pressure and recruitment maneuvers in a ventilator-induced injury mouse model. PLoS ONE 12:20
Zhang N, Zhang Y, Wang L et al (2019) Expression profiling analysis of long noncoding RNAs in a mouse model of ventilator-induced lung injury indicating potential roles in inflammation. J Cell Biochem 120:11660–11679
Ye L, Zeng Q, Dai H et al (2020) Endoplasmic reticulum stress is involved in ventilator-induced lung injury in mice via the IRE1α-TRAF2-NF-κB pathway. Int Immunopharmacol 78:106069
Liu Q, Xie W, Wang Y et al (2019) JAK2/STAT1-mediated HMGB1 translocation increases inflammation and cell death in a ventilator-induced lung injury model. Lab Invest 99:1810–1821
Wu X, Ji H, Wang Y et al (2019) Melatonin alleviates radiation-induced lung injury via regulation of miR-30e/NLRP3 axis. Oxidat Med Cell Longevs 2019:4087298
Liu Y, Guan H, Zhang J et al (2018) Acute downregulation of miR-199a attenuates sepsis-induced acute lung injury by targeting SIRT1. Am J Physiol-Cell Physiol 314:C449–C455
Mao P, Li J, Huang Y et al (2017) MicroRNA-19b mediates lung epithelial-mesenchymal transition via phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase in response to mechanical stretch. Am J Respir Cell Mol Biol 56:11–19
Stevens HC, Deng L, Grant JS et al (2016) Regulation and function of miR-214 in pulmonary arterial hypertension. Pulm Circ 6:109–117
Zhou S, Li M, Zeng D et al (2015) A single nucleotide polymorphism in 3’ untranslated region of epithelial growth factor receptor confers risk for pulmonary hypertension in chronic obstructive pulmonary disease. Cell Physiol Biochem 36:166–178
Cai Z, Zhang S, Zhang Y, Zhou Y, Wu H, Xu X (2012) MicroRNAs are dynamically regulated and play an important role in LPS-induced lung injury. Can J Physiol Pharmacol 90:37–43
Tuerdi B, Zuo L, Ma Y, Wang K (2018) Downregulation of miR-155 attenuates sepsis-induced acute lung injury by targeting SIRT1. Int J Clin Exp Pathol 11:4483
Yu LL, Zhu M, Huang Y et al (2018) Metformin relieves acute respiratory distress syndrome by reducing miR-138 expression. Eur Rev Med Pharmacol Sci 22:5355
Xing X, Li B, Xu S, Liu J, Zhang C, Yang J (2019) MicroRNA-214-3p regulates hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration by targeting ARHGEF12. Med Sci Monit 25:5738–5746
Long H, Wang Z, Chen J et al (2015) microRNA-214 promotes epithelial-mesenchymal transition and metastasis in lung adenocarcinoma by targeting the suppressor-of-fused protein (Sufu). Oncotarget 6:38705–38718
Zhang S, Dai H, Zhu L et al (2018) Microvesicles packaging IL-1β and TNF-α enhance lung inflammatory response to mechanical ventilation in part by induction of cofilin signaling. Int Immunopharmacol 63:74–83
Xie W, Lu Q, Wang K et al (2018) miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin. J Cell Physiol 233:6615–6631
Zhao J, Chen C, Guo M et al (2016) MicroRNA-7 deficiency ameliorates the pathologies of acute lung injury through elevating KLF4. Frontiers in Immunology 7:389–389
Bai M, Chen H, Ding D et al (2019) MicroRNA-214 promotes chronic kidney disease by disrupting mitochondrial oxidative phosphorylation. Kidney Int 95:1389–1404
Zheng D, Zang Y, Xu H et al (2018) MicroRNA-214 promotes the calcification of human aortic valve interstitial cells through the acceleration of inflammatory reactions with activated MyD88/NF-κB signaling. Clin Res Cardiol 108:691–702
Krajisnik T, Olauson H, Mirza MA et al (2010) Parathyroid Klotho and FGF-receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients. Kidney Int 78:1024–1032
Turner CA, Calvo N, Frost DO, Akil H, Watson SJ (2008) The fibroblast growth factor system is downregulated following social defeat. Neurosci Lett 430:147–150
MacKenzie B, Korfei M, Henneke I et al (2015) Increased FGF1-FGFRc expression in idiopathic pulmonary fibrosis. Respir Res 16:83
Fagel DM, Ganat Y, Cheng E et al (2009) Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia. J Neurosci 29:1202–1211
Yang C, Wang C, Ye M et al (2012) Control of lipid metabolism by adipocyte FGFR1-mediated adipohepatic communication during hepatic stress. Nutr Metab 9:94–94
Jiang XL, Du BX, Chen J, Liu L, Shao WB, Song J (2014) MicroRNA-34a negatively regulates anesthesia-induced hippocampal apoptosis and memory impairment through FGFR1. Int J Clin Exp Pathol 7:6760–6767
Hu Y, Liu HX, Jena PK, Sheng L, Ali MR, Wan YY (2020) miR-22 inhibition reduces hepatic steatosis via FGF21 and FGFR1 induction. JHEP Rep 2:100093
Yang Y, Li Z, Yuan H et al (2019) Reciprocal regulatory mechanism between miR-214-3p and FGFR1 in FGFR1-amplified lung cancer. Oncogenesis 8:50
Katoh M (2014) Cardio-miRNAs and onco-miRNAs: circulating miRNA-based diagnostics for non-cancerous and cancerous diseases. Front Cell Dev Biol 2:61–61
Yang L, Ge D, Cao X et al (2016) MiR-214 Attenuates Osteogenic differentiation of mesenchymal stem cells via targeting FGFR1. Cell Physiol Biochem 38:809–820
Li LF, Liu YY, Yang CT et al (2013) Improvement of ventilator-induced lung injury by IPS cell-derived conditioned medium via inhibition of PI3K/Akt pathway and IP-10-dependent paracrine regulation. Biomaterials 34:78–91
Funding
None.
Author information
Authors and Affiliations
Contributions
KH: conception and design and analysis of data. KH and SH: drafting the article. LA and JZ: revising the article critically for important intellectual content. JZ: contributed to the conception of the study. KH and LA: performed the data analyses and wrote the manuscript; SH and JZ: helped perform the analysis with constructive discussions. All the authors read and approved the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical Approval
This study was approved by the ethics committee of The Fourth Hospital of Shijiazhuang.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
He, K., Han, S., An, L. et al. Inhibition of MicroRNA-214 Alleviates Lung Injury and Inflammation via Increasing FGFR1 Expression in Ventilator-Induced Lung Injury. Lung 199, 63–72 (2021). https://doi.org/10.1007/s00408-020-00415-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00408-020-00415-5