Effects of simvastatin on pulmonary fibrosis and endothelial - mesenchymal transition in the pulmonary fibrosis tissue of rats

doi:10.12047/j.cjap.6120.2021.068

Abstract

Abstract: Objective: To investigate the effects of simvastatin (SIM) on pulmonary fibrosis and the expression of VE-cadherin(VE-cad),vimentin(VIM) and alpha-smooth muscle actin(α-SMA)in the pulmonary fibrosis tissue of rats. Methods: Sixty healthy male SD rats were randomly divided into control group(group A), bleomycin group(group B), 5 mg SIM group (group C) and 10 mg SIM group (group D),15 rats in each group. The model of rat pulmonary fibrosis was established by itraperitoneal injection of bleomycin(5 mg/kg). Since the first day of modeling, the rats of group C and D were treated with simvastatin suspension 5 mg/(kg·d) and 10 mg/(kg·d) by intragastric administration everyday, and the rats of group A and B were treated with equal volume of saline 10 ml/(kg·d) everyday. Five rats of each group were sacrificed randomly at the 7th, 14th and 28th day. Masson staining was used to observe the morphological changes of lung tissue in rats. The degree of fibrosis in lung tissues of each group was evaluated by the content of hydroxyproline (HYP) . The microvessel density (MVD) was analyzed by immunohistochemistry,The expressions of protein and mRNA of VE-cad, VIM and α-SMA were determined by immunohistochemistry and RT-PCR. Results: ①Compared with group A, the levels of HYP and MVD, the mRNA and protein expression levels of VIM and α-SMA in lung tissues of groups B, C and D were increased significantly at the 7th, 14th and 28th day(all P＜0.05), which reached highest level at the 28th day. However, the mRNA and protein expression levels of VE-CAD were decreased significantly at the corresponding time (P＜0.05), which reached lowest level at 28th day. ②Compared with group B, the levels of HYP and MVD, the mRNA and protein expression levels of VIM and α-SMA in groups C and D were decreased at the 7th, 14th and 28th day (all P＜0.05), which were decreased more obviously in group D at the 28th day. However, the mRNA and protein expression levels of VE-CAD were increased at the corresponding time (all P＜0.05), which were increased more obviously in group D at the 28th day. Conclusion: Simvastatin can reduce the degree of pulmonary fibrosis in rats through inhibiting the process of EnMT, which can enhance the expression of VE-cad and reduce the expression of VIM and α-SMA.

Key words: pulmonary fibrosis, endothelial-mesenchymal transition, simvastatin, rat

CLC Number:

R563.9

TU Rong-fang, HE Zhen-hua, TAN Xiao-wu, CHEN Zhe, ZENG Sai-li, LIU Sha, JIA Yuan-hang, LI Xue-hua. Effects of simvastatin on pulmonary fibrosis and endothelial - mesenchymal transition in the pulmonary fibrosis tissue of rats[J]. CJAP, 2021, 37(5): 454-459.

References

[1] Wynn TA. Integrating mechanisms of pulmonary fibrosis[J]. J Exp Med, 2011, 208(7): 1339-1350.
[2] Gharaee-Kermani M, Gyetko MR, Hu B, et al. New insights into the pathogenesis and treatment of idiopathic pulmonary fibrosis: a potential role for stem cells in the lung parenchyma and implications for therapy[J]. Pharm Res, 2007, 24(5): 819-841.
[3] King TE Jr, Pardo A, Selman M. Idiopathic pulmonary fibrosis[J]. Lancet, 2011, 378(9807): 1949-1961.
[4] Hashimoto N, Phan SH, Imaizumi K, et al. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis[J]. Am J Respir Cell Mol Biol, 2010, 43(2): 161-172.
[5] Kruzliak P, Hare DL, Zvonicek V, et al. Simvastatin impairs the induction of pulmonary fibrosis caused by a western style diet: a preliminary study[J]. J Cell Mol Med, 2015, 19(11): 2647-2654.
[6] WeisM, Heeschen C, Glassfo rd AJ, et al. Statins have biphasic effects on angiogenesis[J]. Circulation, 2002, 105 (6): 739-745.
[7] 田晟, 曹文富, 张永越, 等. 益气化瘀化痰方对肺纤维化大鼠的干预作用及其机制[J]. 中国应用生理学杂志, 2019, 35(2): 101-106.
[8] Singh S, Adam M, Matkar PN, et al. Endothelial-specific loss of IFT88 promotes endothelial-to-mesenchymal transition and exacerbates bleomycin- induced pulmonary fibrosis[J]. Sci Rep, 2020, 10(1): 1-14.
[9] Weinstein N, Mendoza L, Alvarez-Buylla ER. A computational model of the endothelial to mesenchymal transition[J]. Front Genet, 2020, 11: 40.
[10] Hulshoff MS, Xu X, Krenning G, et al. Epigenetic regulation of endothelial-to-mesenchymal transition in chronic heart disease[J]. Arterioscler Thromb Vasc Biol, 2018, 38(9): 1986-1996.
[11] Lu X, Gong J, Dennery PA, et al. Endothelial-to-mesenchymal transition: Pathogenesis and therapeutic targets for chronic pulmonary and vascular diseases[J]. Biochem Pharmacol, 2019, 168: 100-107.
[12] 蒋荣, 陈明霞. 二氧化硅诱导的内皮间质转化参与矽肺纤维化的实验研究[J]. 现代预防医学, 2020, 47(9): 1665-1669.
[13] Hashimoto N, Phan SH, Imaizumi K, et al. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis[J]. Am J Respir Cell Mol Biol, 2010, 43(2): 161-172.
[14] Jiang Y, Zhou X, Hu R, et al. TGF-β1-induced SMAD 2/3/4 activation promotes RELM-β transcription to modulate the endothelium-mesenchymal transition in human endothelial cells[J]. Int J Biochem Cell Biol, 2018, 105: 52-60.
[15] Sabbineni H, Verma A, Somanath PR. Isoform-specific effects of transforming growth factor β on endothelial-to-mesenchymal transition[J]. J Cell Physiol, 2018, 233(11): 8418-8428.
[16] Piera-Velazquez S, Li Z, Jimenez SA. Role of endothelial-mesenchymal transition (EndoMT) in the pathogenesis of fibrotic disorders[J]. Am J Pathol, 2011, 179 (3): 1074-1080.
[17] 涂容芳, 张秀峰, 何振华. 5-HTR2B、E-cad、α-SMA在博莱霉素致大鼠肺纤维化中的表达变化[J]. 中国应用生理学杂志, 2016, 32(4): 365-369.