The Effects and Mechanism of Atorvastatin in Experimental Pulmonary Fibrosis_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ChenXuefen ¹ ,  JiWenjie ¹ , HuDaochuan ² , MaYongqiang ³ , ZhouXin ³ , PengShouchun ¹ ,  WeiLuqing ¹

1. Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Logistics University of Chinese People's Armed Police Forces, Tianjin, 300162, China;
2. ;
3. ;

Corresponding author：

JiWenjie, Email: ji_wenjie@hotmail.com; WeiLuqing, Email: luqing-wei@163.com

Keywords：

Pulmonary fibrosis; Atorvastatin; Krüppel like factor 4

DOI：

10.7507/1671-6205.2015060

Video：

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Objective To investigate the effects and mechanism of atorvastatin in the experimental pulmonary fibrosis. Methods Fifty-four C57BL/6 mice were randomly divided into a control group,a bleomycin group and an atorvastatin group. The mice in the bleomycin group and the atorvastatin group received a single dose intratracheal injection of bleomycin (2.5 mg/kg),while the mice in the control group were injected with isodose physiological saline. The mice in the atorvastatin group were treated with atorvastatin 10 mg·kg^-1·d^-1 by intragastric administration the day after bleomycin instillation. All groups were sacrificed on the day 3,14 and 28,respectively. HE staining and Masson staining were used to detect the architecture of alveolar and the deposition of cellularity and collagen. RT-PCR and immunohistochemical technology were performed to detect the expression of Krüppel like factor 4 (KLF4). Zymography was used to investigate the activation of matrix metalloproteinase-2(MMP-2). Results After the treatment of bleomycin,the lung tissues showed acute inflammation on the day 3,the collagen deposition was more obvious and the architecture of alveolar was destroyed on the day 14. The alveolar structure,the inflammation and collagen deposition were attenuated on the day 28 compared with the day 14. Compared with the bleomycin group,the inflammation and the collagen deposition were significantly reduced in the atorvastatin group (P<0.05). Compared with bleomycin group,the expression of KLF4 significantly decreased in the atorvastatin group,although the expression of KLF4 mRNA increased on the day 3 compared with the bleomycin group (0.502±0.261 vs. 0.326±0.164,P<0.05). The expression of KLF4 protein on the day 3 was significantly decreased compared with the bleomycin group (0.048±0.015 vs. 0.130±0.017,P<0.05). After the intervention of bleomycin,the activation of MMP-2 on the day 3 and 14 significantly increased compared with the control group (3.136±1.321 and 3.449±0.356 vs. 0.983±0.147,P<0.05),and significantly decreased after the treatment of atorvastatin (2.191±0.800 and 2.506±0.761). Conclusion Atorvastatin may have anti-inflammation and anti-fibrosis activities in experimental pulmonary fibrosis through KLF4 pathway.

Citation： ChenXuefen, JiWenjie, HuDaochuan, MaYongqiang, ZhouXin, PengShouchun, WeiLuqing. The Effects and Mechanism of Atorvastatin in Experimental Pulmonary Fibrosis. Chinese Journal of Respiratory and Critical Care Medicine, 2015, 14(3): 236-241. doi: 10.7507/1671-6205.2015060 Copy

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13.	魏路清,刘斌,李振华,等.阿托伐他汀减轻博莱霉素诱导大鼠实验性肺纤维化.基础医学与临床,2009,29:1198-1202.
14.	魏路清,董彦,李振华.阿托伐他汀对肺纤维化大鼠肺泡灌洗液MMP-9和TIMP-1的影响.浙江大学学报(医学版),2011,40:64-70.
15.	Kim JY,Choeng HC,Ahn C,et al. Early and late changes of MMP-2 and MMP-9 in bleomycin-induced pulmonary fibrosis. Yonsei Med J,2009,50:68-77.
16.	Izidoro-Toledo TC,Guimaraes DA,Belo VA,et al. Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells. Naunyn Schmiedebergs Arch Pharmacol,2011,383:547-554.
17.	陈雪芬,姬文婕,胡道川,等.Krüppel样因子4在实验性肺纤维化小鼠肺组织中的表达及意义.中国呼吸与危重监护杂志,2013,12:509-512.
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1. Haslinger-Loffler B. Multiple effects of HMG-CoA reductase inhibitors (statins) besides their lipid-lowering function. Kidney Int,2008,74:553-555.
2. McConnell BB,Yang VW. Mammalian Krüppel-like factors in health and diseases. Physiol Rev,2010,90:1337-1381.
3. Klein S,Klosel J,Schierwagen R,et al. Atorvastatin inhibits proliferation and apoptosis,but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest,2012,92:1440-1450.
4. Ou XM,Feng YL,Wen FQ,et al. Simvastatin attenuates bleomycin-induced pulmonary fibrosis in mice. Chin Med J (Engl),2008,121:1821-1829.
5. Hamasaki Y,Doi K,Okamoto K,et al. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor simvastatin ameliorates renal fibrosis through HOXA13-USAG-1 pathway. Lab Invest,2012,92:1161-1170.
6. Feinberg MW,Cao Z,Wara AK,et al. Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages. J Biol Chem,2005,280:38247-38258.
7. Alder JK,Georgantas RW 3rd,Hildreth RL,et al. Kruppel-like factor 4 is essential for inflammatory monocyte differentiation in vivo. J Immunol,2008,180:5645-5652.
8. 姬文婕,陈雪芬,马永强,等.Krüppel样因子4基因干扰对RAW264.7细胞凋亡和吞噬的影响.细胞与分子免疫学杂志,2013,29:341-344.
9. Gibbons MA,MacKinnon AC,Ramachandran P,et al.Ly6Chi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis. Am J Respir Crit Care Med,2011,184:569-581.
10. Degryse AL,Lawson WE. Progress toward improving animal models for idiopathic pulmonary fibrosis. Am J Med Sci,2011,341:444-449.
11. Yang T,Chen M,Sun T. Simvastatin attenuates TGF-β1-induced epithelial-mesenchymal transition in human alveolar epithelial cells. Cell Physio Biochem,2013,31:863-874.
12. Zhu B,Ma AQ,Yang L,et al. Atorvastatin attenuates bleomycin-induced pulmonary fibrosis via suppressing iNOS expression and the CTGF (CCN2)/ERK signaling pathway. Int J Mol Sci,2013,14:24476-24491.
13. 魏路清,刘斌,李振华,等.阿托伐他汀减轻博莱霉素诱导大鼠实验性肺纤维化.基础医学与临床,2009,29:1198-1202.
14. 魏路清,董彦,李振华.阿托伐他汀对肺纤维化大鼠肺泡灌洗液MMP-9和TIMP-1的影响.浙江大学学报(医学版),2011,40:64-70.
15. Kim JY,Choeng HC,Ahn C,et al. Early and late changes of MMP-2 and MMP-9 in bleomycin-induced pulmonary fibrosis. Yonsei Med J,2009,50:68-77.
16. Izidoro-Toledo TC,Guimaraes DA,Belo VA,et al. Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells. Naunyn Schmiedebergs Arch Pharmacol,2011,383:547-554.
17. 陈雪芬,姬文婕,胡道川,等.Krüppel样因子4在实验性肺纤维化小鼠肺组织中的表达及意义.中国呼吸与危重监护杂志,2013,12:509-512.
18. Won HH,Kim SR,Bang OY,et al. Differentially expressed genes in human peripheral blood as potential markers for statin response. J Mol Med,2012,90:201-211.

Chinese Journal of Respiratory and Critical Care Medicine

The Effects and Mechanism of Atorvastatin in Experimental Pulmonary Fibrosis

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