Dexmedetomidine represses TGF-β1-induced extracellular matrix production and proliferation of airway smooth muscle cells by inhibiting MAPK signaling pathway
Main Article Content
Keywords
airway smooth muscle cells, dexmedetomidine, extracellular matrix production, proliferation, TGF-β1
Abstract
Background: Airway remodeling is implicated in the pathogenesis of asthma, and abnormal proliferation of airway smooth muscle cells (ASMCs) contribute to airway remodeling. Inflammatory mediator, transforming growth factor-β1 (TGF-β1), stimulates the proliferation of ASMCs, and is associated with airway remodeling in asthma. Dexmedetomidine (DEX) has been widely used in the adjuvant therapy of acute asthma.
Objective: The potential effects of DEX on extracellular matrix (ECM) production and proliferation of ASMCs were investigated in this study.
Material and Methods: Human ASMCs were incubated with TGF-β1 for 48 hours, and then treated with different concentrations of DEX for another 24 hours. Cell proliferation was detected by MTT and BrdU (5’-bromo-2’-deoxyuridine) staining. Flow cytometry was used to assess cell apoptosis, and western blot was applied to identify the underlying mechanism.
Results: TGF-β1 induced increase in cell viability and bromodeoxyuridine (BrdU) positive cells in ASMCs while repressed cell apoptosis. Second, TGF-β1-induced ASMCs were then treated with different concentrations of DEX. Cell viability of TGF-β1-induced ASMCs was decreased by incubation of DEX. The number of BrdU positive cells in TGF-β1-induced ASMCs was reduced by incubation of DEX. Moreover, incubation of DEX promoted cell apoptosis of TGF-β1-induced ASMCs. Third, incubation of DEX attenuated TGF-β1-induced increase in fibronectin, collagen I, MMP9, and versican in ASMCs. Lastly, the up-regulation of phosphorylated extracellular receptor kinase (p-ERK), phosphorylated Jun N-terminal Kinase (p-JNK), and p-p38 in TGF-β1-induced ASMCs was reversed by incubation of DEX.
Conclusion: DEX suppressed TGF-β1-induced ECM production and proliferation of ASMCs through inactivation of p38 mitogen-activated protein kinase (MAPK) pathway, providing a potential strategy for prevention of asthma.
References
2. Hough KP, Curtiss ML, Blain TJ, Liu R-M, Trevor J, Deshane JS, et al. Airway remodeling in asthma. Front Med (Lausanne). 2020;7:191. 10.3389/fmed.2020.00191
3. Bentley JK, Hershenson MB. Airway smooth muscle growth in asthma: Proliferation, hypertrophy, and migration. Proc Am Thorac Soc. 2008;5(1):89–96. 10.1513/pats.200705-063VS
4. Prabhala P, Wright DB, Robbe P, Bitter C, Pera T, Ten Hacken NH, et al. Laminin α4 contributes to airway remodeling and inflammation in asthma. Am J Physiol Lung Cell Mol Physiol. 2019;317(6):L768–77. 10.1152/ajplung.00222.2019
5. Dai Y, Li F, Wu L, Wang R, Li P, Yan S, et al. Roxithromycin treatment inhibits TGF-β1-induced activation of ERK and AKT and down-regulation of Caveolin-1 in rat airway smooth muscle cells. Resp Res. 2014;15:96. 10.1186/s12931-014-0096-z
6. Al-Alawi M, Hassan T, Chotirmall SH. Transforming growth factor β and severe asthma: A perfect storm. Resp Med. 2014;108(10):1409–23. 10.1016/j.rmed.2014.08.008
7. Shen Z-J, Esnault S, Rosenthal LA, Szakaly RJ, Sorkness RL, Westmark PR, et al. Pin1 regulates TGF-β1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J Clin Invest. 2008;118(2):479–90. 10.1172/JCI32789
8. Aron J, Akbari O. Regulatory T cells and type 2 innate lymphoid cell-dependent asthma. Allergy. 2017;72(8):1148–55. 10.1111/all.13139
9. Baarsma HA, Menzen MH, Halayko AJ, Meurs H, Kerstjens HAM, Gosens R. β-Catenin signaling is required for TGF-β1-induced extracellular matrix production by airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2011;301(6):L956–65. 10.1152/ajplung.00123.2011
10. Chen G, Khalil N. TGF-β1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases. Resp Res. 2006;7(1):2. 10.1186/1465-9921-7-2
11. Yang Z, Qu Z, Yi M, Lv Z, Wang Y, Shan Y, et al. MiR-204-5p inhibits transforming growth factor-β1-induced proliferation and extracellular matrix production of airway smooth muscle cells by regulating Six1 in Asthma. Int Arch Allergy Immunol. 2020;181(4):239–48. 10.1159/000505064
12. Lee S. Dexmedetomidine: Present and future directions. Korean J Anesthesiol. 2019;72(4):323–30. 10.4097/kja.19259
13. Si Y, Bao H, Han L, Chen L, Zeng L, Jing L, et al. Dexmedetomidine attenuation of renal ischaemia-reperfusion injury requires sirtuin 3 activation. Br J Anaesth. 2018; 121(6):1260-1271.10.1016/j.bja.2018.07.007
14. Xu Z, Wang D, Zhou Z, Chen Q, Zhang D, Chen S, et al. Dexmedetomidine attenuates renal and myocardial ischemia/reperfusion injury in a dose-dependent manner by inhibiting inflammatory response. Ann Clin Lab Sci. 2019;49:31–5.
15. Yuan M, Meng X-W, Ma J, Liu H, Song S-Y, Chen Q-C, et al. Dexmedetomidine protects H9c2 cardiomyocytes against oxygen-glucose deprivation/reoxygenation-induced intracellular calcium overload and apoptosis through regulating FKBP12. 6/RyR2 signaling.Drug Des Devel Ther. 2019;13:3137–49. 10.2147/DDDT.S219533
16. Zhu C, Zhou Q, Luo C, Chen Y. Dexmedetomidine protects against oxygen-glucose deprivation-induced injury through inducing astrocytes autophagy via TSC2/mTOR pathway. Neuromol Med. 2020;22(2):210–7. 10.1007/s12017-019-08576-0
17. Chen Y, Li L, Zhang J, Cui H, Wang J, Wang C, et al. Dexmedetomidine alleviates lipopolysaccharide-induced hippocampal neuronal apoptosis via inhibiting the p38 MAPK/c-Myc/CLIC4 signaling pathway in rats. Mol Neurobiol. 2021. 58(11):5533-5547. 10.1007/s12035-021-02512-9
18. Hong J, Chen Q, Wang Y, Lin S, Su Y. Dexmedetomidine alleviates smoke-induced bronchial and alveolar epithelial cell injury. Gen Physiol Biophy. 2020;39 3:293–300. 10.4149/gpb_2020003
19. Cozzi G, Lega S, Giorgi R, Barbi E. Intranasal dexmedetomidine sedation as adjuvant therapy in acute asthma exacerbation with marked anxiety and agitation. Ann Emerg Med. 2017;69(1):125–7. 10.1016/j.annemergmed.2016.08.005
20. Takasaki Y, Kido T, Semba K. Dexmedetomidine facilitates induction of noninvasive positive pressure ventilation for acute respiratory failure in patients with severe asthma. J Anesth. 2009;23:314. 10.1007/s00540-008-0712-5;10.1007/s00540-009-0762-3
21. Dai Y, Li F, Wu L, Wang R, Li P, Yan S, et al. Roxithromycin treatment inhibits TGF-β1-induced activation of ERK and AKT and down-regulation of Caveolin-1 in rat airway smooth muscle cells. Respir Res. 2014;15(1):1–8. 10.1186/s12931-014-0096-z
22. Ma D, Rajakumaraswamy N, Maze M. α2-Adrenoceptor agonists: Shedding light on neuroprotection? Br Med Bull. 2005;71(1):77–92. 10.1093/bmb/ldh036
23. Sakai H, Dobashi K, Nakazawa T. Effect of an α2-adrenoceptor antagonist, midaglizole, on bronchial responsiveness to histamine in patients with mild asthma. J Asthma. 1995;32(4):259–64. 10.3109/02770909509044833
24. Groeben H, Mitzner W, Brown Robert H. Effects of the α2-adrenoceptor agonist dexmedetomidine on bronchoconstriction in dogs. Anesthesiology. 2004;100(2):359–63. 10.1097/00000542-200402000-00026
25. Zhang H, Yan HL, Li XY, Guo YN. TNFSF14, a novel target of miR-326, facilitates airway remodeling in airway smooth muscle cells via inducing extracellular matrix protein deposition and proliferation. Kaohsiung J Med Sciences. 2020;36(7):508–14. 10.1002/kjm2.12197
26. Yu Q, Li Q, Yang X, Liu Q, Deng J, Zhao Y, et al. Dexmedetomidine suppresses the development of abdominal aortic aneurysm by downregulating the mircoRNA-21/PDCD 4 axis. Int J Mol Med. 2021;47(5):1–11. 10.3892/ijmm.2021.4923
27. Lv X, Li Y, Gong Q, Jiang Z. TGF-β1 induces airway smooth muscle cell proliferation and remodeling in asthmatic mice by up-regulating miR-181a and suppressing PTEN. Int J Clin Exp Pathol. 2019;12(1):173.
28. Laping N, Grygielko E, Mathur A, Butter S, Bomberger J, Tweed C, et al. Inhibition of transforming growth factor (TGF)-β1-induced extracellular matrix with a novel inhibitor of the TGF-β type I receptor kinase activity: SB-431542. Mol Pharmacol. 2002;62(1):58–64. 10.1124/mol.62.1.58
29. Zhang P, He H, Bai Y, Liu W, Huang L. Dexmedetomidine suppresses the progression of esophageal cancer via miR-143-3p/epidermal growth factor receptor pathway substrate 8 axis. Anticancer Drugs. 2020;31(7):693–701. 10.1097/CAD.0000000000000934
30. Chi M, Shi X, Huo X, Wu X, Zhang P, Wang G. Dexmedetomidine promotes breast cancer cell migration through Rab11-mediated secretion of exosomal TMPRSS2. Ann Transl Med. 2020;8(8):531. 10.21037/atm.2020.04.28
31. Chen M, Shi J-T, Lv Z-Q, Huang L-J, Lin X-L, Zhang W, et al. Triptolide inhibits transforming growth factor-β1-induced proliferation and migration of rat airway smooth muscle cells by suppressing nuclear factor-κB but not extracellular signal-regulated kinase 1/2. Immunology. 2015;144(3):486–94. 10.1111/imm.12396
32. Manzoor MK, Eric BP. The role of mitogen-activated protein kinases in asthma. Curr Immunol Rev. 2015;11(2):132–46. 10.2174/1573395511666150615225641
33. Khorasanizadeh M, Eskian M, Gelfand E, Rezaei N. Mitogen-activated protein kinases as therapeutic targets for asthma. Pharmacol Ther. 2017; 174:112-126. 10.1016/j.pharmthera.2017.02.024
34. Dai Y, Li F, Wu L, Wang R, Li P, Yan S, et al. Roxithromycin treatment inhibits TGF-β1-induced activation of ERK and AKT and down-regulation of Caveolin-1 in rat airway smooth muscle cells. Resp Res. 2014;15(1):96. 10.1186/s12931-014-0096-z
35. Sun Y, Shi Z, Liu B, Li XG, Li G, Yang F, et al. YKL-40 mediates airway remodeling in asthma via activating FAK and MAPK signaling pathway. Cell Cycle. 2020;19(11):1378–90. 10.1080/15384101.2020.1750811
36. Wang Q, Tan Y, Zhang N, Xu Y, Wei W, She Y, et al. Dexmedetomidine inhibits activation of the MAPK pathway and protects PC12 and NG108-15 cells from lidocaine-induced cytotoxicity at its maximum safe dose. Biomed Pharmacother. 2017;91:162–6. 10.1016/j.biopha.2017.04.084
37. Liao Z, Cao D, Han X, Liu C, Peng J, Zuo Z, et al. Both JNK and P38 MAPK pathways participate in the protection by dexmedetomidine against isoflurane-induced neuroapoptosis in the hippocampus of neonatal rats. Brain Res Bull. 2014;107:69–78. 10.1016/j.brainresbull.2014.07.001
38. Cai Q-H, Tang Y, Fan S-H, Zhang Z-F, Li H, Huang S-Q, et al. In vivo effects of dexmedetomidine on immune function and tumor growth in rats with ovarian cancer through inhibiting the p38MAPK/NF-κB signaling pathway. Biomed Pharmacother. 2017;95:1830–7. 10.1016/j.biopha.2017.09.086
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