右美托咪定通过抑制 MAPK 信号通路抑制 TGF-β1 诱导的细胞外基质产生和气道平滑肌细胞增殖。
Dexmedetomidine represses TGF-β1-induced extracellular matrix production and proliferation of airway smooth muscle cells by inhibiting MAPK signaling pathway.
机构信息
Department of Anesthesiology, Rugao Hospital of Traditional Chinese Medicine, Nantong, Jiangsu, China.
Department of Anesthesiology, Rugao Hospital of Traditional Chinese Medicine, Nantong, Jiangsu, China;
出版信息
Allergol Immunopathol (Madr). 2022 Mar 1;50(2):16-22. doi: 10.15586/aei.v50i2.505. eCollection 2022.
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.
背景
气道重塑与哮喘的发病机制有关，气道平滑肌细胞（ASMCs）的异常增殖导致气道重塑。炎症介质转化生长因子-β1（TGF-β1）刺激 ASMCs 的增殖，并与哮喘中的气道重塑有关。右美托咪定（DEX）已广泛应用于急性哮喘的辅助治疗。
目的
本研究旨在探讨 DEX 对 ASMCs 细胞外基质（ECM）产生和增殖的潜在作用。
材料和方法
将人 ASMCs 与 TGF-β1 孵育 48 小时，然后用不同浓度的 DEX 再处理 24 小时。通过 MTT 和 BrdU（5'-溴-2'-脱氧尿苷）染色检测细胞增殖。采用流式细胞术评估细胞凋亡，Western blot 用于鉴定潜在机制。
结果
TGF-β1 诱导 ASMCs 活力增加和 BrdU 阳性细胞增多，同时抑制细胞凋亡。其次，用不同浓度的 DEX 处理 TGF-β1 诱导的 ASMCs。TGF-β1 诱导的 ASMCs 中，DEX 孵育降低细胞活力。TGF-β1 诱导的 ASMCs 中 BrdU 阳性细胞的数量减少。此外，DEX 孵育促进 TGF-β1 诱导的 ASMCs 细胞凋亡。第三，DEX 减弱 TGF-β1 诱导的 ASMCs 中纤维连接蛋白、胶原 I、MMP9 和 versican 的增加。最后，DEX 孵育逆转 TGF-β1 诱导的 ASMCs 中磷酸化细胞外受体激酶（p-ERK）、磷酸化 Jun N-末端激酶（p-JNK）和 p-p38 的上调。
结论
DEX 通过抑制 p38 丝裂原活化蛋白激酶（MAPK）通路抑制 TGF-β1 诱导的 ECM 产生和 ASMCs 增殖，为预防哮喘提供了一种潜在策略。
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