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apoptosis, AQP1, inflammation, MEF2C, sepsis
Background: Sepsis is a systemic inflammatory response syndrome and leads to patient’s death.Objective: To investigate the effect of myocyte enhancer factor 2 (MEF2C) on acute lung injury (ALI) with sepsis and its possible mechanism.
Material and Methods: The cecal ligation and puncture (CLP)-induced sepsis rat model was established. The lung injury was determined by lung wet–dry weight ratio, the concentration of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), Interlukin (IL)-6, IL-1β, and IL-10, were measured by the enzyme-linked-immunosorbent serologic assay kit. The cell apoptosis was detected by TUNEL staining assay.
Results: Interestingly, MEF2C was down-regulated in this model. Moreover, adeno-associated virus (AAV)-MEF2C treatment markedly suppressed TNF-α, IL-1β, and IL-6 concentrations but promoted IL-10 concentration in serum in CLP-challenged rats. Besides, overexpression of MEF2C alleviates CLP-induced lung injury. Interestingly, AAV-MEF2C treatment was confirmed to suppress apoptosis in CLP-induced sepsis rats as well as promote aquaporin APQ1 expression. Mechanistically, the rescue experiments indicated that MEF2C alleviated CLP-induced lung inflammatory response and apoptosis via up-regulating AQP1.
Conclusion: In summary, overexpression of MEF2C suppressed CLP-induced lung inflammatory response and apoptosis via up-regulating AQP1, providing a novel therapeutic target for sepsis-induced ALI.
2. Kaplan MY, Ozen S, Akcal O, Gulez N, Genel F. Autoimmune and inflammatory manifestations in pediatric patients with primary immunodeficiencies and their importance as a warning sign. Allergologia et Immunopathol. 2020;48(6):701–10. https://doi.org/10.1016/j.aller.2020.02.009
3. Olvera L, Dutra D. Early recognition and management of maternal sepsis. Nurs Women's Health. 2016;20(2):182–95; quiz 96. https://doi.org/10.1016/j.nwh.2016.02.003.
4. Han IM, Yoon CY, Shin DH, Kee YK, Han SG, Kwon YE, et al. Delta neutrophil index is an independent predictor of mortality in septic acute kidney injury patients treated with continuous renal replacement therapy. BMC Nephrol. 2017;18(1):94. https://doi.org/10.1186/s12882-017-0507-8
5. Li R, Ren T, Zeng J. Mitochondrial coenzyme Q protects sepsis-induced acute lung injury by activating PI3K/Akt/GSK-3beta/mTOR pathway in rats. BioMed Res Int. 2019;2019:5240898. https://doi.org/10.1155/2019/5240898
6. Deczkowska A, Matcovitch-Natan O, Tsitsou-Kampeli A, Ben-Hamo S, Dvir-Szternfeld R, Spinrad A, et al. Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner. Nat Commun. 2017;8(1):717. https://doi.org/10.1038/s41467-017-00769-0
7. Xu Z, Yoshida T, Wu L, Maiti D, Cebotaru L, Duh EJ. Transcription factor MEF2C suppresses endothelial cell inflammation via regulation of NF-kappaB and KLF2. J Cell Physiol. 2015;230(6):1310–20. https://doi.org/10.1002/jcp.24870
8. Sahoo S, Meijles DN, Al Ghouleh I, Tandon M, Cifuentes-Pagano E, Sembrat J, et al. MEF2C-MYOCD and Leiomodin1 suppression by miRNA-214 promotes smooth muscle cell phenotype switching in pulmonary arterial hypertension. PloS One. 2016;11(5):e0153780. https://doi.org/10.1371/journal.pone.0153780.
9. Hua Y, Ying X, Qian Y, Liu H, Lan Y, Xie A, et al. Physiological and pathological impact of AQP1 knockout in mice. Biosci Rep. 2019 May;39(5):BSR20182303. https://doi.org/10.1042/BSR20182303
10. Kang X, Lu XG, Zhan LB, Liang ZK, Guo WX, Ma Q, et al. Dai-Huang-Fu-Zi-Tang alleviates pulmonary and intestinal injury with severe acute pancreatitis via regulating aquaporins in rats. BMC Compl Altern Med. 2017;17(1):288. https://doi.org/10.1186/s12906-017-1789-x
11. Gao Z, Xu J, Sun D, Zhang R, Liang R, Wang L, et al. Traditional Chinese medicine, Qing Ying Tang, ameliorates the severity of acute lung injury induced by severe acute pancreatitis in rats via the upregulation of aquaporin-1. Exp Ther Med. 2014;8(6):1819–24. https://doi.org/10.3892/etm.2014.1987
12. Jiang Y, Ma R, Zhao Y, Li GJ, Wang AK, Lin WL, et al. MEF2C/miR-133a-3p.1 circuit-stabilized AQP1 expression maintains endothelial water homeostasis. FEBS Lett. 2019;593(18):2566–73. https://doi.org/10.1002/1873-3468.13516
13. Williams AE, Chambers RC. The mercurial nature of neutrophils: Still an enigma in ARDS? Am J Physiol Lung Cell Mol Physiol. 2014;306(3):L217–30. https://doi.org/10.1152/ajplung.00311.2013
14. Xia W, Pan Z, Zhang H, Zhou Q, Liu Y. Inhibition of ERRalpha aggravates sepsis-induced acute lung injury in rats via provoking inflammation and oxidative stress. Oxid Med Cell Long. 2020;2020:2048632. https://doi.org/10.1155/2020/2048632
15. Chen X, Cai X, Le R, Zhang M, Gu X, Shen F, et al. Isoliquiritigenin protects against sepsis-induced lung and liver injury by reducing inflammatory responses. Biochem Biophy Res Comm. 2018;496(2):245–52. https://doi.org/10.1016/j.bbrc.2017.11.159
16. Zheng H, Liang W, He W, Huang C, Chen Q, Yi H, et al. Ghrelin attenuates sepsis-induced acute lung injury by inhibiting the NF-kappaB, iNOS, and Akt signaling in alveolar macrophages. Am J Physiol Lung Cell Mol Physiol. 2019;317(3):L381–91. https://doi.org/10.1152/ajplung.00253.2018
17. Park KS, Svennerholm K, Shelke GV, Bandeira E, Lasser C, Jang SC, et al. Mesenchymal stromal cell-derived nanovesicles ameliorate bacterial outer membrane vesicle-induced sepsis via IL-10. Stem Cell Res Ther. 2019;10(1):231. https://doi.org/10.1186/s13287-019-1352-4
18. Girardot T, Rimmele T, Venet F, Monneret G. Apoptosis-induced lymphopenia in sepsis and other severe injuries. Apoptosis Int J Prog Cell Death. 2017;22(2):295–305. https://doi.org/10.1007/s10495-016-1325-3
19. Cao C, Yu M, Chai Y. Pathological alteration and therapeutic implications of sepsis-induced immune cell apoptosis. Cell Death Dis. 2019;10(10):782. https://doi.org/10.1038/s41419-019-2015-1
20. Mahidhara R, Billiar TR. Apoptosis in sepsis. Crit Care Med. 2000;28(4 Suppl): N105–13. https://doi.org/10.1097/00003246-200004001-00013.
21. Li Z, Jia Y, Feng Y, Cui R, Miao R, Zhang X, et al. Methane alleviates sepsis-induced injury by inhibiting pyroptosis and apoptosis: In vivo and in vitro experiments. Aging. 2019;11(4):1226–39. https://doi.org/10.18632/aging.101831
22. Jiang WY, Ren J, Zhang XH, Lu ZL, Feng HJ, Yao XL, et al. CircC3P1 attenuated pro-inflammatory cytokine production and cell apoptosis in acute lung injury induced by sepsis through modulating miR-21. J Cell Mol Med. 2020;24(19):11221–9. https://doi.org/10.1111/jcmm.15685
23. Chopra M, Reuben JS, Sharma AC. Acute lung injury: Apoptosis and signaling mechanisms. Exp Biol Med. 2009;234(4):361–71. https://doi.org/10.3181/0811-MR-318
24. Hong-Min F, Chun-Rong H, Rui Z, Li-Na S, Ya-Jun W, Li L. CGRP 8-37 enhances lipopolysaccharide-induced acute lung injury and regulating aquaporin 1 and 5 expressions in rats. J Physiol Biochem. 2016;73(3):381–6. https://doi.org/10.1007/s13105-017-0563-3
25. Ma T, Liu Z. Functions of aquaporin 1 and alpha-epithelial Na+ channel in rat acute lung injury induced by acute ischemic kidney injury. Int Urol Nephrol. 2013;45(4):1187–96. https://doi.org/10.1007/s11255-012-0355-1
26. Tao B, Liu L, Wang N, Wang W, Jiang J, Zhang J. Effects of hydrogen-rich saline on aquaporin 1, 5 in septic rat lungs. J Surg Res. 2016;202(2):291–8. https://doi.org/10.1016/j.jss.2016.01.009
27. Fisher BJ, Kraskauskas D, Martin EJ, Farkas D, Wegelin JA, Brophy D, et al. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol. 2012;303(1):L20–32. https://doi.org/10.1152/ajplung.00300.2011.
28. Guo R, Li Y, Han M, Liu J, Sun Y. Emodin attenuates acute lung injury in cecal-ligation and puncture rats. Int Immunopharm. 2020;85:106626. https://doi.org/10.1016/j.intimp.2020.106626
29. Liu D, Wang Y, Li L, Zhao H, Li L, Liu Y, et al. Celecoxib protects hyperoxia-induced lung injury via NF-kappaB and AQP1. Front Pediatr. 2019;7:228. https://doi.org/10.3389/fped.2019.00228
30. Li H, Shi H, Gao M, Ma N, Sun R. Long non-coding RNA CASC2 improved acute lung injury by regulating miR-144-3p/AQP1 axis to reduce lung epithelial cell apoptosis. Cell Biosci. 2018;8:15. https://doi.org/10.1186/s13578-018-0205-7
31. Ma C, Dong L, Li M, Cai W. Qidonghuoxue decoction ameliorates pulmonary edema in acute lung injury mice through the upregulation of epithelial sodium channel and aquaporin-1. Evidence Complement Altern Med (eCAM). 2020;2020:2492304. https://doi.org/10.1155/2020/2492304
32. Jiang Y, Liu H, Liu WJ, Tong HB, Chen CJ, Lin FG, et al. Endothelial aquaporin-1 (AQP1) expression is regulated by transcription factor Mef2c. Mol Cells. 2016;39(4):292–8. https://doi.org/10.14348/molcells.2016.2223
33. Li X, Su J, Cui X, Li Y, Barochia A, Eichacker PQ. Can we predict the effects of NF-kappaB inhibition in sepsis? Studies with parthenolide and ethyl pyruvate. Expert Opin Invest Drugs. 2009;18(8):1047–60. https://doi.org/10.1517/13543780903018880