Schisandrin B attenuates bleomycin-induced pulmonary fibrosis in mice through AKT-mTOR pathway
Main Article Content
Keywords
pulmonary fibrosis, bleomycin, autophagy
Abstract
Purpose: Schisandrin B (Sch B) is an active monomer of Schisandrin with anti-fibrosis pharmacological action. The study investigated whether Sch B alleviate bleomycin-induced (BLM-Induced) pulmonary fibrosis in mice and attempted to clarify its anti-fibrosis mechanism. Methods: Histopathological examination was performed by H&E staining and immunohistochemistry. The inflammatory cytokines and oxidative stress were determined by ELISA. Western blotting and immunofluorescence were used to investigate the possible molecular mechanism to attenuate pulmonary fibrosis by Sch B. Results: The results indicated that Sch B can significantly attenuate BLM-Induced pulmonary fibrosis, myofibroblast activation, and collagen fibers deposition in mice. In addition, Sch B can inhibit inflammatory response and oxidative stress in early stage. Furthermore, Sch B can inhibit pulmonary fibrosis by promoting autophagy via promoting the dephosphorylation of AKT-mTOR pathway. Conclusions: The results suggest that the anti-fibrotic effect of Sch B is potentially related to the activation of autophagy through AKT-mTOR pathway, and Sch B is a potential agent for the treatment of idiopathic pulmonary fibrosis.
References
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20. De Andrade J, Luckhardt T, Sonavane S, Crowe DR, Kulkarni T, Acosta Lara MDP, et al. Evaluating the consistency with guideline recommendations for diagnosis and management of idiopathic pulmonary fibrosis in non-academic settings. Sarcoidosis Vasc Diffuse Lung Dis. 2023;40(1):e2023003. Epub 2023/03/29. doi: 10.36141/svdld.v40i1.11460. PubMed PMID: 36975060; PubMed Central PMCID: PMCPMC10099650 consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article.
21. Wang K, Zhang T, Lei Y, Li X, Jiang J, Lan J, et al. Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux. Autophagy. 2018;14(2):269-82. Epub 2017/11/28. doi: 10.1080/15548627.2017.1409405. PubMed PMID: 29172997; PubMed Central PMCID: PMCPMC5902212.
22. Lee S, Chun JN, Lee HJ, Park HH, So I, Jeon JH, et al. Transcriptome Analysis of the Anti-TGFbeta Effect of Schisandra chinensis Fruit Extract and Schisandrin B in A7r5 Vascular Smooth Muscle Cells. Life (Basel). 2021;11(2). Epub 2021/03/07. doi: 10.3390/life11020163. PubMed PMID: 33672474; PubMed Central PMCID: PMCPMC7926316.
23. Valero-Jimenez A, Zuniga J, Cisneros J, Becerril C, Salgado A, Checa M, et al. Transmembrane protease, serine 4 (TMPRSS4) is upregulated in IPF lungs and increases the fibrotic response in bleomycin-induced lung injury. PLoS One. 2018;13(3):e0192963. Epub 2018/03/13. doi: 10.1371/journal.pone.0192963. PubMed PMID: 29529050; PubMed Central PMCID: PMCPMC5846721.
24. You S, Qian J, Wu G, Qian Y, Wang Z, Chen T, et al. Schizandrin B attenuates angiotensin II induced endothelial to mesenchymal transition in vascular endothelium by suppressing NF-kappaB activation. Phytomedicine. 2019;62:152955. Epub 2019/05/31. doi: 10.1016/j.phymed.2019.152955. PubMed PMID: 31146168.
25. Zhou Y, Li P, Duan JX, Liu T, Guan XX, Mei WX, et al. Aucubin Alleviates Bleomycin-Induced Pulmonary Fibrosis in a Mouse Model. Inflammation. 2017;40(6):2062-73. Epub 2017/08/09. doi: 10.1007/s10753-017-0646-x. PubMed PMID: 28785877.
26. Leask A. Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res. 2010;106(11):1675-80. Epub 2010/06/12. doi: 10.1161/CIRCRESAHA.110.217737. PubMed PMID: 20538689.
27. Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S. Evaluating the Ameliorative Potential of Quercetin against the Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats. Pulm Med. 2013;2013:921724. Epub 2014/01/08. doi: 10.1155/2013/921724. PubMed PMID: 24396596; PubMed Central PMCID: PMCPMC3875129.
28. Mouratis MA, Aidinis V. Modeling pulmonary fibrosis with bleomycin. Curr Opin Pulm Med. 2011;17(5):355-61. Epub 2011/08/13. doi: 10.1097/MCP.0b013e328349ac2b. PubMed PMID: 21832918.
29. Liu W, Wan J, Han JZ, Li C, Feng DD, Yue SJ, et al. Antiflammin-1 attenuates bleomycin-induced pulmonary fibrosis in mice. Respir Res. 2013;14(1):101. Epub 2013/10/09. doi: 10.1186/1465-9921-14-101. PubMed PMID: 24098933; PubMed Central PMCID: PMCPMC3856527.
30. Chitra P, Saiprasad G, Manikandan R, Sudhandiran G. Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-kappaB dependant TGF-beta activation: a biphasic experimental study. Toxicol Lett. 2013;219(2):178-93. Epub 2013/03/26. doi: 10.1016/j.toxlet.2013.03.009. PubMed PMID: 23523906.
31. Haspel JA, Choi AM. Autophagy: a core cellular process with emerging links to pulmonary disease. Am J Respir Crit Care Med. 2011;184(11):1237-46. Epub 2011/08/13. doi: 10.1164/rccm.201106-0966CI. PubMed PMID: 21836133; PubMed Central PMCID: PMCPMC3262043.
32. Korfhagen TR, Le Cras TD, Davidson CR, Schmidt SM, Ikegami M, Whitsett JA, et al. Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2009;41(5):562-72. Epub 2009/02/27. doi: 10.1165/rcmb.2008-0377OC. PubMed PMID: 19244201; PubMed Central PMCID: PMCPMC2778163.
33. Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol. 1962;12(1):198-202. Epub 1962/01/01. doi: 10.1083/jcb.12.1.198. PubMed PMID: 13862833; PubMed Central PMCID: PMCPMC2106008.
34. Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, et al. Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2013;304(1):L56-69. Epub 2012/10/23. doi: 10.1152/ajplung.00213.2012. PubMed PMID: 23087019.
35. Ching JK, Weihl CC. Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. Autophagy. 2013;9(5):799-800. Epub 2013/02/27. doi: 10.4161/auto.23958. PubMed PMID: 23439279; PubMed Central PMCID: PMCPMC3669194.
36. Li X, Wu D, Shen J, Zhou M, Lu Y. Rapamycin induces autophagy in the melanoma cell line M14 via regulation of the expression levels of Bcl-2 and Bax. Oncol Lett. 2013;5(1):167-72. Epub 2012/12/21. doi: 10.3892/ol.2012.986. PubMed PMID: 23255914; PubMed Central PMCID: PMCPMC3525347.
2. Aloufi N, Traboulsi H, Ding J, Fonseca GJ, Nair P, Huang SK, et al. Angiotensin-converting enzyme 2 expression in COPD and IPF fibroblasts: the forgotten cell in COVID-19. Am J Physiol Lung Cell Mol Physiol. 2021;320(1):L152-L7. Epub 2020/10/29. doi: 10.1152/ajplung.00455.2020. PubMed PMID: 33112187; PubMed Central PMCID: PMCPMC7869954.
3. Molyneaux PL, Maher TM. Respiratory microbiome in IPF: cause, effect, or biomarker? Lancet Respir Med. 2014;2(7):511-3. Epub 2014/04/29. doi: 10.1016/S2213-2600(14)70088-8. PubMed PMID: 24767768.
4. Samarelli AV, Tonelli R, Heijink I, Martin Medina A, Marchioni A, Bruzzi G, et al. Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis: Cause or Solution. Front Pharmacol. 2021;12:692551. Epub 2021/07/23. doi: 10.3389/fphar.2021.692551. PubMed PMID: 34290610; PubMed Central PMCID: PMCPMC8287856.
5. Cilli A, Uzer F. Disease progression in idiopathic pulmonary fibrosis under anti-fibrotic treatment. Sarcoidosis Vasc Diffuse Lung Dis. 2023;40(3):e2023034. Epub 2023/09/15. doi: 10.36141/svdld.v40i3.14048. PubMed PMID: 37712374; PubMed Central PMCID: PMCPMC10540722.
6. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015;192(2):e3-19. Epub 2015/07/16. doi: 10.1164/rccm.201506-1063ST. PubMed PMID: 26177183.
7. Jiang EP, Li H, Yu CR, Yu CY, Jing S, Sun HX, et al. Schisandrin B protects PC12 cells against oxidative stress of neurodegenerative diseases. Neuroreport. 2015;26(6):360-6. Epub 2015/03/11. doi: 10.1097/WNR.0000000000000354. PubMed PMID: 25756908.
8. Leong PK, Ko KM. Schisandrin B: A Double-Edged Sword in Nonalcoholic Fatty Liver Disease. Oxid Med Cell Longev. 2016;2016:6171658. Epub 2016/11/17. doi: 10.1155/2016/6171658. PubMed PMID: 27847552; PubMed Central PMCID: PMCPMC5101399.
9. Li L, Pan Q, Han W, Liu Z, Li L, Hu X. Schisandrin B prevents doxorubicin-induced cardiotoxicity via enhancing glutathione redox cycling. Clin Cancer Res. 2007;13(22 Pt 1):6753-60. Epub 2007/11/17. doi: 10.1158/1078-0432.CCR-07-1579. PubMed PMID: 18006777.
10. Chiu PY, Leung HY, Siu AH, Poon MK, Ko KM. Schisandrin B decreases the sensitivity of mitochondria to calcium ion-induced permeability transition and protects against ischemia-reperfusion injury in rat hearts. Acta Pharmacol Sin. 2007;28(10):1559-65. Epub 2007/09/22. doi: 10.1111/j.1745-7254.2007.00614.x. PubMed PMID: 17883940.
11. Nasser MI, Zhu S, Chen C, Zhao M, Huang H, Zhu P. A Comprehensive Review on Schisandrin B and Its Biological Properties. Oxid Med Cell Longev. 2020;2020:2172740. Epub 2020/04/08. doi: 10.1155/2020/2172740. PubMed PMID: 32256947; PubMed Central PMCID: PMCPMC7102409.
12. Zhu H, Zhang X, Guan J, Cui B, Zhao L, Zhao X. Pharmacokinetics and tissue distribution study of schisandrin B in rats by ultra-fast liquid chromatography with tandem mass spectrometry. J Pharm Biomed Anal. 2013;78-79:136-40. Epub 2013/03/12. doi: 10.1016/j.jpba.2013.01.041. PubMed PMID: 23474814.
13. Li WL, Xin HW, Yu AR, Wu XC. In vivo effect of Schisandrin B on cytochrome P450 enzyme activity. Phytomedicine. 2013;20(8-9):760-5. Epub 2013/03/26. doi: 10.1016/j.phymed.2013.02.005. PubMed PMID: 23523258.
14. Wang Y, Dong X, Zhao N, Su X, Wang Y, Li Y, et al. Schisandrin B attenuates bleomycin-induced pulmonary fibrosis in mice through the wingless/integrase-1 signaling pathway. Exp Lung Res. 2020;46(6):185-94. Epub 2020/05/05. doi: 10.1080/01902148.2020.1760964. PubMed PMID: 32362157.
15. Patel AS, Lin L, Geyer A, Haspel JA, An CH, Cao J, et al. Autophagy in idiopathic pulmonary fibrosis. PLoS One. 2012;7(7):e41394. Epub 2012/07/21. doi: 10.1371/journal.pone.0041394. PubMed PMID: 22815997; PubMed Central PMCID: PMCPMC3399849.
16. Walters DM, Kleeberger SR. Mouse models of bleomycin-induced pulmonary fibrosis. Curr Protoc Pharmacol. 2008;Chapter 5:Unit 5 46. Epub 2008/03/01. doi: 10.1002/0471141755.ph0546s40. PubMed PMID: 22294226.
17. Lee JG, Shin JH, Shim HS, Lee CY, Kim DJ, Kim YS, et al. Autophagy contributes to the chemo-resistance of non-small cell lung cancer in hypoxic conditions. Respir Res. 2015;16:138. Epub 2015/11/11. doi: 10.1186/s12931-015-0285-4. PubMed PMID: 26553068; PubMed Central PMCID: PMCPMC4640373.
18. Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol. 2008;40(3):362-82. Epub 2007/10/16. doi: 10.1016/j.biocel.2007.08.011. PubMed PMID: 17936056; PubMed Central PMCID: PMCPMC2323681.
19. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988;41(4):467-70. Epub 1988/04/01. doi: 10.1136/jcp.41.4.467. PubMed PMID: 3366935; PubMed Central PMCID: PMCPMC1141479.
20. De Andrade J, Luckhardt T, Sonavane S, Crowe DR, Kulkarni T, Acosta Lara MDP, et al. Evaluating the consistency with guideline recommendations for diagnosis and management of idiopathic pulmonary fibrosis in non-academic settings. Sarcoidosis Vasc Diffuse Lung Dis. 2023;40(1):e2023003. Epub 2023/03/29. doi: 10.36141/svdld.v40i1.11460. PubMed PMID: 36975060; PubMed Central PMCID: PMCPMC10099650 consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article.
21. Wang K, Zhang T, Lei Y, Li X, Jiang J, Lan J, et al. Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux. Autophagy. 2018;14(2):269-82. Epub 2017/11/28. doi: 10.1080/15548627.2017.1409405. PubMed PMID: 29172997; PubMed Central PMCID: PMCPMC5902212.
22. Lee S, Chun JN, Lee HJ, Park HH, So I, Jeon JH, et al. Transcriptome Analysis of the Anti-TGFbeta Effect of Schisandra chinensis Fruit Extract and Schisandrin B in A7r5 Vascular Smooth Muscle Cells. Life (Basel). 2021;11(2). Epub 2021/03/07. doi: 10.3390/life11020163. PubMed PMID: 33672474; PubMed Central PMCID: PMCPMC7926316.
23. Valero-Jimenez A, Zuniga J, Cisneros J, Becerril C, Salgado A, Checa M, et al. Transmembrane protease, serine 4 (TMPRSS4) is upregulated in IPF lungs and increases the fibrotic response in bleomycin-induced lung injury. PLoS One. 2018;13(3):e0192963. Epub 2018/03/13. doi: 10.1371/journal.pone.0192963. PubMed PMID: 29529050; PubMed Central PMCID: PMCPMC5846721.
24. You S, Qian J, Wu G, Qian Y, Wang Z, Chen T, et al. Schizandrin B attenuates angiotensin II induced endothelial to mesenchymal transition in vascular endothelium by suppressing NF-kappaB activation. Phytomedicine. 2019;62:152955. Epub 2019/05/31. doi: 10.1016/j.phymed.2019.152955. PubMed PMID: 31146168.
25. Zhou Y, Li P, Duan JX, Liu T, Guan XX, Mei WX, et al. Aucubin Alleviates Bleomycin-Induced Pulmonary Fibrosis in a Mouse Model. Inflammation. 2017;40(6):2062-73. Epub 2017/08/09. doi: 10.1007/s10753-017-0646-x. PubMed PMID: 28785877.
26. Leask A. Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res. 2010;106(11):1675-80. Epub 2010/06/12. doi: 10.1161/CIRCRESAHA.110.217737. PubMed PMID: 20538689.
27. Verma R, Kushwah L, Gohel D, Patel M, Marvania T, Balakrishnan S. Evaluating the Ameliorative Potential of Quercetin against the Bleomycin-Induced Pulmonary Fibrosis in Wistar Rats. Pulm Med. 2013;2013:921724. Epub 2014/01/08. doi: 10.1155/2013/921724. PubMed PMID: 24396596; PubMed Central PMCID: PMCPMC3875129.
28. Mouratis MA, Aidinis V. Modeling pulmonary fibrosis with bleomycin. Curr Opin Pulm Med. 2011;17(5):355-61. Epub 2011/08/13. doi: 10.1097/MCP.0b013e328349ac2b. PubMed PMID: 21832918.
29. Liu W, Wan J, Han JZ, Li C, Feng DD, Yue SJ, et al. Antiflammin-1 attenuates bleomycin-induced pulmonary fibrosis in mice. Respir Res. 2013;14(1):101. Epub 2013/10/09. doi: 10.1186/1465-9921-14-101. PubMed PMID: 24098933; PubMed Central PMCID: PMCPMC3856527.
30. Chitra P, Saiprasad G, Manikandan R, Sudhandiran G. Berberine attenuates bleomycin induced pulmonary toxicity and fibrosis via suppressing NF-kappaB dependant TGF-beta activation: a biphasic experimental study. Toxicol Lett. 2013;219(2):178-93. Epub 2013/03/26. doi: 10.1016/j.toxlet.2013.03.009. PubMed PMID: 23523906.
31. Haspel JA, Choi AM. Autophagy: a core cellular process with emerging links to pulmonary disease. Am J Respir Crit Care Med. 2011;184(11):1237-46. Epub 2011/08/13. doi: 10.1164/rccm.201106-0966CI. PubMed PMID: 21836133; PubMed Central PMCID: PMCPMC3262043.
32. Korfhagen TR, Le Cras TD, Davidson CR, Schmidt SM, Ikegami M, Whitsett JA, et al. Rapamycin prevents transforming growth factor-alpha-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2009;41(5):562-72. Epub 2009/02/27. doi: 10.1165/rcmb.2008-0377OC. PubMed PMID: 19244201; PubMed Central PMCID: PMCPMC2778163.
33. Ashford TP, Porter KR. Cytoplasmic components in hepatic cell lysosomes. J Cell Biol. 1962;12(1):198-202. Epub 1962/01/01. doi: 10.1083/jcb.12.1.198. PubMed PMID: 13862833; PubMed Central PMCID: PMCPMC2106008.
34. Araya J, Kojima J, Takasaka N, Ito S, Fujii S, Hara H, et al. Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol. 2013;304(1):L56-69. Epub 2012/10/23. doi: 10.1152/ajplung.00213.2012. PubMed PMID: 23087019.
35. Ching JK, Weihl CC. Rapamycin-induced autophagy aggravates pathology and weakness in a mouse model of VCP-associated myopathy. Autophagy. 2013;9(5):799-800. Epub 2013/02/27. doi: 10.4161/auto.23958. PubMed PMID: 23439279; PubMed Central PMCID: PMCPMC3669194.
36. Li X, Wu D, Shen J, Zhou M, Lu Y. Rapamycin induces autophagy in the melanoma cell line M14 via regulation of the expression levels of Bcl-2 and Bax. Oncol Lett. 2013;5(1):167-72. Epub 2012/12/21. doi: 10.3892/ol.2012.986. PubMed PMID: 23255914; PubMed Central PMCID: PMCPMC3525347.
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Zhou D, Hu J, Yang DH, Cai Y, Lu Q. Schisandrin B attenuates bleomycin-induced pulmonary fibrosis in mice through AKT-mTOR pathway. Sarcoidosis Vasc Diffuse Lung Dis [Internet]. 2024 Sep. 24 [cited 2024 Dec. 26];41(3):e2024034. Available from: https://mattioli1885journals.com/index.php/sarcoidosis/article/view/12728
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How to Cite
1.
Zhou D, Hu J, Yang DH, Cai Y, Lu Q. Schisandrin B attenuates bleomycin-induced pulmonary fibrosis in mice through AKT-mTOR pathway. Sarcoidosis Vasc Diffuse Lung Dis [Internet]. 2024 Sep. 24 [cited 2024 Dec. 26];41(3):e2024034. Available from: https://mattioli1885journals.com/index.php/sarcoidosis/article/view/12728
