miR‑374a‑5p alleviates sepsis‑induced acute lung injury by targeting ZEB1 via the p38 MAPK pathway

Shen,Jia; Ma,Xiaojun

doi:10.3892/etm.2022.11501

miR‑374a‑5p alleviates sepsis‑induced acute lung injury by targeting ZEB1 via the p38 MAPK pathway

Authors:
- Jia Shen
- Xiaojun Ma
View Affiliations

Affiliations: Department of Intensive Care Unit, General Hospital of Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750002, P.R. China, Department of Orthopedics, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia Hui Autonomous Region 750004, P.R. China
Published online on: July 12, 2022 https://doi.org/10.3892/etm.2022.11501
Article Number: 564
Copyright: © Shen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to investigate the effects of microRNA (miR)‑374a‑5p on sepsis‑induced acute lung injury (ALI) and the associated mechanism. Lipopolysaccharide (LPS)‑induced human pulmonary microvascular endothelial cells (HPMVECs) were used to construct the cellular model of sepsis. A luciferase reporter assay was performed to confirm the association between miR‑374a‑5p and zinc finger E‑box binding homeobox 1 (ZEB1). Reverse transcription‑quantitative polymerase chain reaction and western blot analysis were performed to assess the relative expression of miR‑374a‑5p, ZEB1 and apoptosis‑related proteins. Cell viability and apoptosis were determined by Cell Counting Kit‑8 assay and flow cytometry, respectively. Enzyme‑linked immunosorbent assays were used to evaluate inflammatory cytokines. The results revealed that miR‑374a‑5p was downregulated in sepsis patients and LPS‑treated HPMVECs. Upregulation of miR‑374a‑5p alleviated LPS‑triggered cell injury in HPMVECs, as evidenced by restoration of cell viability, and inhibition of apoptosis and the production of proinflammatory cytokines. In addition, ZEB1 was revealed to be a downstream target of miR‑374a‑5p, and overexpression of ZEB1 could reverse the anti‑apoptotic and anti‑inflammatory effects of miR‑374a‑5p on an LPS‑induced sepsis cell model. Moreover, miR‑374a‑5p‑induced protective effects involved the p38 MAPK signaling pathway. Collectively, miR‑374a‑5p exerted a protective role in sepsis‑induced ALI by regulating the ZEB1‑mediated p38 MAPK signaling pathway, providing a potential target for the diagnosis and treatment of sepsis.

View Figures

View References

1	Liu KD and Matthay MA: Advances in critical care for the nephrologist: Acute lung injury/ARDS. Clin J Am Soc Nephrol. 3:578–586. 2008.PubMed/NCBI View Article : Google Scholar
2	Gotts JE and Matthay MA: Sepsis: Pathophysiology and clinical management. BMJ. 353(i1585)2016.PubMed/NCBI View Article : Google Scholar
3	Yang L, Zhang Z, Zhuo Y, Cui L, Li C, Li D, Zhang S, Cui N, Wang X and Gao H: Resveratrol alleviates sepsis-induced acute lung injury by suppressing inflammation and apoptosis of alveolar macrophage cells. Am J Transl Res. 10:1961–1975. 2018.PubMed/NCBI
4	Wang RH, Xie YX, Qiu JW and Chen JY: Influence of LincRNA-p21 on acute lung injury in sepsis. Eur Rev Med Pharmacol Sci. 24:5618–5626. 2020.PubMed/NCBI View Article : Google Scholar
5	Huang LS, Hong Z, Wu W, Xiong S, Zhong M, Gao X, Rehman J and Malik AB: mtDNA activates cGAS signaling and suppresses the YAP-mediated endothelial cell proliferation program to promote inflammatory injury. Immunity. 52:475–486.e5. 2020.PubMed/NCBI View Article : Google Scholar
6	Cen M, Ouyang W, Zhang W, Yang L, Lin X, Dai M, Hu H, Tang H, Liu H, Xia J and Xu F: MitoQ protects against hyperpermeability of endothelium barrier in acute lung injury via a Nrf2-dependent mechanism. Redox Biol. 41(101936)2021.PubMed/NCBI View Article : Google Scholar
7	Nova Z, Skovierova H and Calkovska A: Alveolar-capillary membrane-related pulmonary cells as a target in endotoxin-induced acute lung injury. Int J Mol Sci. 20(831)2019.PubMed/NCBI View Article : Google Scholar
8	Lu Q, Zhang D, Liu H and Xu H: miR-942-5p prevents sepsis-induced acute lung injury via targeting TRIM37. Int J Exp Pathol. 102:192–199. 2021.PubMed/NCBI View Article : Google Scholar
9	Vishnoi A and Rani S: MiRNA biogenesis and regulation of diseases: An overview. Methods Mol Biol. 1509:1–10. 2017.PubMed/NCBI View Article : Google Scholar
10	Chunlei H, Chang Z, Sheng L, Yanchun Z, Lulin L and Daozhang C: Down-regulation of MiR-138-5p Protects Chondrocytes ATDC5 and CHON-001 from IL-1 β-induced inflammation via up-regulating SOX9. Curr Pharm Des. 25:4613–4621. 2020.PubMed/NCBI View Article : Google Scholar
11	Qu SP, Li GW, Ma H and Xing Q: MicroRNA-193a-3p participates in the progression of rheumatoid arthritis by regulating proliferation and apoptosis of MH7A cells through targeting IGFBP5. Eur Rev Med Pharmacol Sci. 23:4850–4857. 2019.PubMed/NCBI View Article : Google Scholar
12	Han Y, Li Y and Jiang Y: The prognostic value of plasma microRNA-155 and microRNA-146a level in severe sepsis and sepsis-induced acute lung injury patients. Clin Lab. 62:2355–2360. 2016.PubMed/NCBI View Article : Google Scholar
13	Wu H, Liu Y, Shu XO and Cai Q: MiR-374a suppresses lung adenocarcinoma cell proliferation and invasion by targeting TGFA gene expression. Carcinogenesis. 37:567–575. 2016.PubMed/NCBI View Article : Google Scholar
14	Xu Z, Xu J, Lu H, Lin B, Cai S, Guo J, Zang F and Chen R: LARP1 is regulated by the XIST/miR-374a axis and functions as an oncogene in non-small cell lung carcinoma. Oncol Rep. 38:3659–3667. 2017.PubMed/NCBI View Article : Google Scholar
15	Zhao M, Xu P, Liu Z, Zhen Y, Chen Y, Liu Y, Fu Q, Deng X, Liang Z, Li Y, et al: Dual roles of miR-374a by modulated c-Jun respectively targets CCND1-inducing PI3K/AKT signal and PTEN-suppressing Wnt/β-catenin signaling in non-small-cell lung cancer. Cell Death Dis. 9(78)2018.PubMed/NCBI View Article : Google Scholar
16	Xiong Y, Qiu J, Li C, Qiu Y, Guo L, Liu Y, Wan J, Li Y, Wu G, Wang L, et al: Fortunellin-induced modulation of phosphatase and tensin homolog by microRNA-374a decreases inflammation and maintains intestinal barrier function in colitis. Front Immunol. 9(83)2018.PubMed/NCBI View Article : Google Scholar
17	Chen Z, Hu Y, Lu R, Ge M and Zhang L: MicroRNA-374a-5p inhibits neuroinflammation in neonatal hypoxic-ischemic encephalopathy via regulating NLRP3 inflammasome targeted Smad6. Life Sci. 252(117664)2020.PubMed/NCBI View Article : Google Scholar
18	Adyshev DM, Moldobaeva N, Mapes B, Elangovan V and Garcia JG: MicroRNA regulation of nonmuscle myosin light chain kinase expression in human lung endothelium. Am J Respir Cell Mol Biol. 49:58–66. 2013.PubMed/NCBI View Article : Google Scholar
19	Gao Y, Zhao Y, Zhang J, Lu Y, Liu X, Geng P, Huang B, Zhang Y and Lu J: The dual function of PRMT1 in modulating epithelial-mesenchymal transition and cellular senescence in breast cancer cells through regulation of ZEB1. Sci Rep. 6(19874)2016.PubMed/NCBI View Article : Google Scholar
20	Liu Y, El-Naggar S, Darling DS, Higashi Y and Dean DC: Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development. 135:579–588. 2008.PubMed/NCBI View Article : Google Scholar
21	Fu R, Lv WC, Xu Y, Gong MY, Chen XJ, Jiang N, Xu Y, Yao QQ, Di L, Lu T, et al: Endothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis. Nat Commun. 11(460)2020.PubMed/NCBI View Article : Google Scholar
22	Matsui S, Zhou L, Nakayama Y, Mezawa M, Kato A, Suzuki N, Tanabe N, Nakayama T, Suzuki Y, Kamio N, et al: MiR-200b attenuates IL-6 production through IKKβ and ZEB1 in human gingival fibroblasts. Inflamm Res. 67:965–973. 2018.PubMed/NCBI View Article : Google Scholar
23	Yang J, Tao Q, Zhou Y, Chen Q, Li L, Hu S, Liu Y, Zhang Y, Shu J, Zhang X, et al: MicroRNA-708 represses hepatic stellate cells activation and proliferation by targeting ZEB1 through Wnt/β-catenin pathway. Eur J Pharmacol. 871(172927)2020.PubMed/NCBI View Article : Google Scholar
24	Lin LP, Niu GH and Zhang XQ: Influence of lncRNA MALAT1 on septic lung injury in mice through p38 MAPK/p65 NF-κB pathway. Eur Rev Med Pharmacol Sci. 23:1296–1304. 2019.PubMed/NCBI View Article : Google Scholar
25	Hu XH, Situ HL, Chen JP and Yu RH: Lipoxin A4 alleviates lung injury in sepsis rats through p38/MAPK signaling pathway. J Biol Regul Homeost Agents. 34:807–814. 2020.PubMed/NCBI View Article : Google Scholar
26	Shao Y, Chen X, Liu Y, Chen X, Li C, Wang L and Zhao W: Dexmedetomidine alleviates lung injury in sepsis mice through regulating P38 MAPK signaling pathway. Panminerva Med. 63:563–564. 2021.PubMed/NCBI View Article : Google Scholar
27	Cao Y, Liu Y, Ping F, Yi L, Zeng Z and Li Y: miR-200b/c attenuates lipopolysaccharide-induced early pulmonary fibrosis by targeting ZEB1/2 via p38 MAPK and TGF-β/smad3 signaling pathways. Lab Invest. 98:339–359. 2018.PubMed/NCBI View Article : Google Scholar
28	Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al: The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA. 315:801–810. 2016.PubMed/NCBI View Article : Google Scholar
29	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
30	Crowley LC, Marfell BJ, Scott AP and Waterhouse NJ: Quantitation of apoptosis and necrosis by annexin V binding, propidium iodide uptake, and flow cytometry. Cold Spring Harb Protoc. 2016:953–957. 2016.PubMed/NCBI View Article : Google Scholar
31	Mu S, Liu Y, Jiang J, Ding R, Li X, Li X and Ma X: Unfractionated heparin ameliorates pulmonary microvascular endothelial barrier dysfunction via microtubule stabilization in acute lung injury. Respir Res. 19(220)2018.PubMed/NCBI View Article : Google Scholar
32	Li X, Jamal M, Guo P, Jin Z, Zheng F, Song X, Zhan J and Wu H: Irisin alleviates pulmonary epithelial barrier dysfunction in sepsis-induced acute lung injury via activation of AMPK/SIRT1 pathways. Biomed Pharmacother. 118(109363)2019.PubMed/NCBI View Article : Google Scholar
33	Jiang F, Yang M, Wu C and Wang J: Potential roles of miR-374a-5p in mediating neuroprotective effects and related molecular mechanism. J Mol Neurosci. 69:123–132. 2019.PubMed/NCBI View Article : Google Scholar
34	Chen YQ, Yang X, Xu W, Yan Y, Chen XM and Huang ZQ: Knockdown of lncRNA TTTY15 alleviates myocardial ischemia-reperfusion injury through the miR-374a-5p/FOXO1 axis. IUBMB Life. 73:273–285. 2021.PubMed/NCBI View Article : Google Scholar
35	Huang ZQ, Xu W, Wu JL, Lu X and Chen XM: MicroRNA-374a protects against myocardial ischemia-reperfusion injury in mice by targeting the MAPK6 pathway. Life Sci. 232(116619)2019.PubMed/NCBI View Article : Google Scholar
36	Doumatey AP, He WJ, Gaye A, Lei L, Zhou J, Gibbons GH, Adeyemo A and Rotimi CN: Circulating MiR-374a-5p is a potential modulator of the inflammatory process in obesity. Sci Rep. 8(7680)2018.PubMed/NCBI View Article : Google Scholar
37	Voss AK and Strasser A: The essentials of developmental apoptosis. F1000Res. 9(F1000)2020.PubMed/NCBI View Article : Google Scholar
38	Wu X, Kong Q, Zhan L, Qiu Z, Huang Q and Song X: TIPE2 ameliorates lipopolysaccharide-induced apoptosis and inflammation in acute lung injury. Inflamm Res. 68:981–992. 2019.PubMed/NCBI View Article : Google Scholar
39	Li D, Lang W, Zhou C, Wu C, Zhang F, Liu Q, Yang S and Hao J: Upregulation of microglial ZEB1 ameliorates brain damage after acute ischemic stroke. Cell Rep. 22:3574–3586. 2018.PubMed/NCBI View Article : Google Scholar
40	de Barrios O, Sanchez-Moral L, Cortés M, Ninfali C, Profitós-Pelejà N, Martínez-Campanario MC, Siles L, Del Campo R, Fernández-Aceñero MJ, Darling DS, et al: ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells. Gut. 68:2129–2141. 2019.PubMed/NCBI View Article : Google Scholar
41	Chen IC, Wang SC, Chen YT, Tseng HH, Liu PL, Lin TC, Wu HE, Chen YR, Tseng YH, Hsu JH, et al: Corylin ameliorates LPS-induced acute lung injury via suppressing the MAPKs and IL-6/STAT3 signaling pathways. Pharmaceuticals (Basel). 14(1046)2021.PubMed/NCBI View Article : Google Scholar