Role of microRNA‑15a‑5p/TNFAIP3‑interacting protein&nbsp;2 axis in acute lung injury induced by traumatic hemorrhagic shock

Zhou,Feng; Liu,Zhizhen; Cai,Huazhong; Miao,Zhenjun; Wei,Faxing; Song,Chao

doi:10.3892/etm.2020.9130

Role of microRNA‑15a‑5p/TNFAIP3‑interacting protein 2 axis in acute lung injury induced by traumatic hemorrhagic shock

Authors:
- Feng Zhou
- Zhizhen Liu
- Huazhong Cai
- Zhenjun Miao
- Faxing Wei
- Chao Song
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Affiliations: Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China
Published online on: August 25, 2020 https://doi.org/10.3892/etm.2020.9130
Article Number: 2
Copyright: © Zhou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to investigate the role of microRNA (miR)‑15a‑5p in the pathogenesis of acute lung injury induced by traumatic hemorrhagic shock (THS), and to explore the underlying molecular mechanism. The expression level of miR‑15a‑5p was detected using reverse transcription‑quantitative (RT‑qPCR) and the association between miR‑15a‑5p and TNFAIP3‑interacting protein 2 (TNIP2) was revealed using TargetScan and dual luciferase reporter assays. To investigate the effect of miR‑15a‑5p on THS‑induced acute lung injury, a THS rat model was established. Lung capillary permeability and lung edema were then determined. Moreover, proinflammatory factors in the bronchoalveolar lavage fluid (BALF) and serum of the THS rat model were detected using ELISA. In addition, protein levels in the current study were measured via western blotting. It was revealed that miR‑15a‑5p was significantly upregulated in both patients with THS and samples from the THS rat model. TNIP2 represents a direct target of miR‑15a‑5p, and it was downregulated in both patients with THS and the THS rat model. Further analyses indicated that downregulation of miR‑15a‑5p significantly relieved acute lung injury induced by THS, evidenced by a decreased ratio of Evan's blue dye (EBD) in the BALF to EBD in plasma of THS rats, decreased lung permeability index and reduced lung wet/dry ratio. Inhibition of miR‑15a‑5p also decreased THS‑induced upregulation of pro‑inflammatory factors. Furthermore, the data revealed that THS‑induced NF‑κB activation in the lung tissues of rats was inhibited by miR‑15a‑5p knockdown. Moreover, it was demonstrated that all the effects of miR‑15a‑5p on THS rats were ablated following TNIP2 silencing. Taken together, the data of the current study indicate that miR‑15a‑5p downregulation serves a protective role in THS‑induced acute lung injury via directly targeting TNIP2.

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1	Kauvar DS, Lefering R and Wade CE: Impact of hemorrhage on trauma outcome: An overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma. 60 (Suppl 6):S3–S11. 2006.PubMed/NCBI View Article : Google Scholar
2	Kauvar DS and Wade CE: The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care. 9 (Suppl 5):S1–S9. 2005.PubMed/NCBI View Article : Google Scholar
3	Angele MK, Schneider CP and Chaudry IH: Bench-to-bedside review: Latest results in hemorrhagic shock. Crit Care. 12(218)2008.PubMed/NCBI View Article : Google Scholar
4	Cai B, Deitch EA and Ulloa L: Novel insights for systemic inﬂammation in sepsis and hemorrhage. Mediators Inflamm. 2010(642462)2010.PubMed/NCBI View Article : Google Scholar
5	Ananthakrishnan P, Cohen DB, Xu DZ, Lu Q, Feketeova E and Deitch EA: Sex hormones modulate distant organ injury in both a trauma/hemorrhagic shock model and a burn model. Surgery. 137:56–65. 2005.PubMed/NCBI View Article : Google Scholar
6	Cheifetz IM: Year in review 2015: Pediatric ARDS. Respir Care. 61:980–985. 2016.PubMed/NCBI View Article : Google Scholar
7	Hoegl S, Brodsky KS, Blackburn MR, Karmouty-Quintana H, Zwissler B and Eltzschig HK: Alveolar epithelial A2B adenosine receptors in pulmonary protection during acute lung injury. J Immunol. 195:1815–1824. 2015.PubMed/NCBI View Article : Google Scholar
8	De Luca D, Piastra M, Tosi F, Pulitanò S, Mancino A, Genovese O, Pietrini D and Conti G: Pharmacological therapies for pediatric and neonatal ALI/ARDS: An evidence-based review. Curr Drug Targets. 13:906–916. 2012.PubMed/NCBI View Article : Google Scholar
9	Lee CC, Chang IJ, Yen ZS, Hsu CY, Chen SY, Su CP, Chiang WC, Chen SC and Chen WJ: Delayed ﬂuid resuscitation in hemorrhagic shock induces proinﬂammatory cytokine response. Ann Emerg Med. 49:37–44. 2007.PubMed/NCBI View Article : Google Scholar
10	Claridge JA, Schulman AM and Young JS: Improved resuscitation minimizes respiratory dysfunction and blunts interleukin6 and nuclear factor-kappa B activation after traumatic hemorrhage. Crit Care Med. 30:1815–1819. 2002.PubMed/NCBI View Article : Google Scholar
11	Jiang H, Huang Y, Xu H, Hu R and Li QF: Inhibition of hypoxia inducible factor-1α ameliorates lung injury induced by trauma and hemorrhagic shock in rats. Acta Pharmacol Sin. 33:635–643. 2012.PubMed/NCBI View Article : Google Scholar
12	Koscsó B, Trepakov A, Csóka B, Németh ZH, Pacher P, Eltzschig HK and Haskó G: Stimulation of A2B adenosine receptors protects against trauma-hemorrhagic shock-induced lung injury. Purinergic Signal. 9:427–432. 2013.PubMed/NCBI View Article : Google Scholar
13	Hammond SM: An overview of microRNAs. Adv Drug Deliv Rev. 87:3–14. 2015.PubMed/NCBI View Article : Google Scholar
14	Soifer HS, Rossi JJ and Saetrom P: MicroRNAs in disease and potential therapeutic applications. Mol Ther. 15:2070–2079. 2017.PubMed/NCBI View Article : Google Scholar
15	Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010.PubMed/NCBI View Article : Google Scholar
16	O'Connell RM, Rao DS, Chaudhuri AA and Baltimore D: Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol. 10:111–122. 2010.PubMed/NCBI View Article : Google Scholar
17	Tutar Y: miRNA and cancer; computational and experimental approaches. Curr Pharm Biotechnol. 15(429)2014.PubMed/NCBI View Article : Google Scholar
18	Vickers KC, Rye KA and Tabet F: MicroRNAs in the onset and development of cardiovascular disease. Clin Sci (Lond). 126:183–194. 2014.PubMed/NCBI View Article : Google Scholar
19	Zhang J, Liu Y and Lu L: Emerging role of microRNAs in peripheral nerve system. Life Sci. 207:227–233. 2018.PubMed/NCBI View Article : Google Scholar
20	Karolina DS, Tavintharan S, Armugam A, Sepramaniam S, Pek SLT, Wong MTK, Lim SC, Sum CF and Jeyaseelan K: Circulating miRNA profiles in patients with metabolic syndrome. J Clin Endocrinol Metab. 97:E2271–E2276. 2012.PubMed/NCBI View Article : Google Scholar
21	Wang W, Tang S, Li H, Liu R, Su Y, Shen L, Sun M and Ning B: MicroRNA-21a-5p promotes fibrosis in spinal fibroblasts after mechanical trauma. Exp Cell Res. 370:24–30. 2018.PubMed/NCBI View Article : Google Scholar
22	Ferruelo A, Peñuelas Ó and Lorente JA: MicroRNAs as biomarkers of acute lung injury. Ann Transl Med. 6(34)2018.PubMed/NCBI View Article : Google Scholar
23	Wang ZM, Wan XH, Sang GY, Zhao JD, Zhu QY and Wang DM: miR-15a-5p suppresses endometrial cancer cell growth via Wnt/β-catenin signaling pathway by inhibiting WNT3A. Eur Rev Med Pharmacol Sci. 21:4810–4818. 2017.PubMed/NCBI
24	Chen D, Wu D, Shao K, Ye B, Huang J and Gao Y: MiR-15a-5p negatively regulates cell survival and metastasis by targeting CXCL10 in chronic myeloid leukemia. Am J Transl Res. 9:4308–4316. 2017.PubMed/NCBI
25	Long J, Jiang C, Liu B, Fang S and Kuang M: MicroRNA-15a-5p suppresses cancer proliferation and division in human hepatocellular carcinoma by targeting BDNF. Tumour Biol. 37:5821–5828. 2016.PubMed/NCBI View Article : Google Scholar
26	Kontos CK, Tsiakanikas P, Avgeris M, Papadopoulos IN and Scorilas A: miR-15a-5p, a novel prognostic biomarker, predicting recurrent colorectal adenocarcinoma. Mol Diagn Ther. 21:453–464. 2017.PubMed/NCBI View Article : Google Scholar
27	Verstrepen L, Carpentier I, Verhelst K and Beyaert R: ABINs: A20 binding inhibitors of NF-kappa B and apoptosis signaling. Biochem Pharmacol. 78:105–114. 2009.PubMed/NCBI View Article : Google Scholar
28	Xie H, Yang M, Zhang B, Liu M and Han S: Protective role of TNIP2 in myocardial injury induced by acute pancreatitis and its mechanism. Med Sci Monit. 23:5650–5656. 2017.PubMed/NCBI View Article : Google Scholar
29	Wang W, Gao J and Wang F: MiR-663a/MiR-423-5p are involved in the pathogenesis of lupus nephritis via modulating the activation of NF-κB by targeting TNIP2. Am J Transl Res. 9:3796–3803. 2017.PubMed/NCBI
30	Guo S, Jiang K, Wu H, Yang C, Yang Y, Yang J, Zhao G and Deng G: Magnoflorine ameliorates lipopolysaccharide-induced acute lung injury via suppressing NF-κB and MAPK activation. Front Pharmacol. 9(982)2018.PubMed/NCBI View Article : Google Scholar
31	Yu J, Ni L, Zhang X, Zhang J, Abdel-Razek O and Wang G: Surfactant protein D dampens lung injury by suppressing NLRP3 inflammasome activation and NF-κB signaling in acute pancreatitis. Shock. 51:557–568. 2018.PubMed/NCBI View Article : Google Scholar
32	Yang G, Peng X, Hu Y, Lan D, Wu Y, Li T and Liu L: 4-phenylbutyrate benefits traumatic hemorrhagic shock in rats by attenuating oxidative stress, not by attenuating endoplasmic reticulum stress. Crit Care Med. 44:e477–e491. 2016.PubMed/NCBI View Article : Google Scholar
33	Shi HP, Deitch EA, Da Xu Z, Lu Q and Hauser CJ: Hypertonic saline improves intestinal mucosa barrier function and lung injury after trauma-hemorrhagic shock. Shock. 17:496–501. 2002.PubMed/NCBI View Article : Google Scholar
34	Liu WJ, Zhong ZJ, Cao LH, Li HT, Zhang TH and Lin WQ: Paclitaxel-induced lung injury and its amelioration by parecoxib sodium. Sci Rep. 5(12977)2015.PubMed/NCBI View Article : Google Scholar
35	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
36	Senthil M, Watkins A, Barlos D, Xu DZ, Lu Q, Abungu B, Caputo F, Feinman R and Deitch EA: Intravenous injection of trauma-hemorrhagic shock mesenteric lymph causes lung injury that is dependent upon activation of the inducible nitric oxide synthase pathway. Ann Surg. 246:822–830. 2007.PubMed/NCBI View Article : Google Scholar
37	Vallabhapurapu S and Karin M: Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol. 27:693–733. 2009.PubMed/NCBI View Article : Google Scholar
38	Mariappan N, Elks CM, Sriramula S, Guggilam A, Liu Z, Borkhsenious O and Francis J: NF-kappaB-induced oxidative stress contributes to mitochondrial and cardiac dysfunction in type II diabetes. Cardiovasc Res. 85:473–483. 2010.PubMed/NCBI View Article : Google Scholar
39	Pateras I, Giaginis C, Tsigris C, Patsouris E and Theocharis S: NF-κB signaling at the crossroads of inflammation and atherogenesis: Searching for new therapeutic links. Expert Opin Ther Targets. 18:1089–1101. 2014.PubMed/NCBI View Article : Google Scholar