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,劉斌,李振華,等.阿托伐他汀減輕博萊霉素誘導大鼠實驗性肺纖維化.基礎醫學與臨床,2009,29:1198-1202.
14.	魏路清,董彥,李振華.阿托伐他汀對肺纖維化大鼠肺泡灌洗液MMP-9和TIMP-1的影響.浙江大學學報(醫學版),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.	陳雪芬,姬文婕,胡道川,等.Krüppel樣因子4在實驗性肺纖維化小鼠肺組織中的表達及意義.中國呼吸與危重監護雜志,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,陳雪芬,馬永強,等.Krüppel樣因子4基因干擾對RAW264.7細胞凋亡和吞噬的影響.細胞與分子免疫學雜志,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,劉斌,李振華,等.阿托伐他汀減輕博萊霉素誘導大鼠實驗性肺纖維化.基礎醫學與臨床,2009,29:1198-1202.
14. 魏路清,董彥,李振華.阿托伐他汀對肺纖維化大鼠肺泡灌洗液MMP-9和TIMP-1的影響.浙江大學學報(醫學版),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. 陳雪芬,姬文婕,胡道川,等.Krüppel樣因子4在實驗性肺纖維化小鼠肺組織中的表達及意義.中國呼吸與危重監護雜志,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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