본문 바로가기
KERD
논문KCI 등재

Improved anti-fibrotic effects by combined treatments of simvastatin and NS-398 in experimental liver fibrosis models

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류내과학

초록

Background/Aims: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl- coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl- 2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions: The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

Abstract

Background/Aims: Efficient anti-fibrotic therapies are required for the treatment of liver cirrhosis. Hydroxymethylglutaryl- coenzyme A reductase inhibitors (statins) and cyclooxygenase-2 (COX-2) inhibitors have been reported to have anti-fibrotic effects. Here, we investigated whether combined treatment with a statin and a COX-2 inhibitor has synergistic anti-fibrotic effects. Methods: The effects of treatment strategies incorporating both simvastatin and a COX-2 inhibitor, NS-398, were investigated using an immortalized human hepatic stellate cell line (LX-2) and a hepatic fibrosis mouse model developed using thioacetamide (TAA) in drinking water. Cellular proliferation was investigated via 5-bromo-2-deoxyuridine uptake. Pro- and anti-apoptotic factors were investigated through Western blotting and real-time polymerase chain reaction analysis. Results: The evaluation of the anti-proliferative effects on LX-2 cells showed that the observed effects were more pronounced with combination therapy than with single-drug therapy. Moreover, hepatic fibrosis and collagen deposition decreased significantly in TAA-treated mice in response to the combined treatment strategy. The mechanisms underlying the anti-fibrotic effects of the combination therapy were investigated. The effects of the combination therapy were correlated with increased expression levels of extracellular signal-regulated kinase 1/2 signaling molecules, upregulation of the Bax/Bcl- 2 signaling pathway, inhibition of the transforming growth factor-β signaling pathway, and inhibition of tissue inhibitor of matrix metalloproteinases 1 and 2. Conclusions: The combination of simvastatin and NS-398 resulted in a synergistic anti-fibrotic effect through multiple pathways. These findings offer a theoretical insight into the possible clinical application of this strategy for the treatment of advanced liver diseases with hepatic fibrosis.

참고문헌 (36)

  1. Arthur MJ, "Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C", Gastroenterology, 122, pp.1525~1528 (2002)
  2. Kweon YO, "Decreasing fibrogenesis : an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B", J Hepatol, 35, pp.749~755 (2001)
  3. 정영걸, "Reversal of liver cirrhosis: current evidence and expectations", The Korean Journal of Internal Medicine, 32(2), pp.213~228 (2017), 대한내과학회[DOI]
  4. Friedman SL, "Mechanisms of hepatic fibrogenesis", Gastroenterology, 134, pp.1655~1669 (2008)
  5. Saile B, "Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells", Hepatology, 30, pp.196~202 (1999)
  6. Costa AM, "Role of apoptosis in the remodeling of cholestatic liver injury following release of the mechanical stress", Virchows Arch, 442, pp.372~380 (2003)
  7. Fan X, "Attenuation of CCl4-induced hepatic fibrosis in mice by vaccinating against TGF-β1", PLoS One, 8, pp.e82190~ (2013)
  8. Lan T, "Deficiency of NOX1 or NOX4 prevents liver inflammation and fibrosis in mice through inhibition of hepatic stellate cell activation", PLoS One, 10, pp.e0129743~ (2015)
  9. Barry-Hamilton V, "Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment", Nat Med, 16, pp.1009~1017 (2010)
  10. Lee SJ, "Synergistic effect of simvastatin plus NS398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line", J Gastroenterol Hepatol, 29, pp.1299~1307 (2014)
  11. Nogaki F, "Direct inhibitory effects of simvastatin on matrix accumulation in cultured murine mesangial cells", Kidney Int Suppl, 71, pp.S198~S201 (1999)
  12. Park HJ, "3-Hydroxy-3-methylglutaryl CoA reductase inhibitors up-regulate transforming growth factor-beta signaling in cultured heart cells via inhibition of geranylgeranylation of RhoA GTPase", Proc Natl Acad Sci U S A, 96, pp.11525~11530 (1999)
  13. Yoshimura A, "Effect of simvastatin on proliferative nephritis and cell-cycle protein expression", Kidney Int Suppl, 71, pp.S84~S87 (1999)
  14. Hawkey CJ, "COX-2 inhibitors", Lancet, 353, pp.307~314 (1999)
  15. Hui AY, "Effect of celecoxib on experimental liver fibrosis in rat", Liver Int, 26, pp.125~136 (2006)
  16. Friedman SL, "Liver fibrosis : from bench to bedside", J Hepatol, 38(Suppl 1), pp.S38~S53 (2003)
  17. Schellenberg B, "Bax exists in a dynamic equilibrium between the cytosol and mitochondria to control apoptotic priming", Mol Cell, 49, pp.959~971 (2013)
  18. Santibanez JF, "Transforming growth factor-beta1 modulates matrix metalloproteinase-9 production through the Ras", MAPK signaling pathway in transformed keratinocytes, 2002, pp.296, 267~273
  19. Hemmann S, "Expression of MMPs and TIMPs in liver fibrosis : a systematic review with special emphasis on anti-fibrotic strategies", J Hepatol, 46, pp.955~975 (2007)
  20. Garcia-Ruiz I, "Sp1and Sp3 transcription factors mediate leptin-induced collagen α1(I)gene expression in primary culture of male rat hepatic stellate cells", Endocrinology, 153, pp.5845~5856 (2012)
  21. Aprigliano I, "Atorvastatin induces apoptosis by a caspase-9-dependent pathway : an in vitro study on activated rat hepatic stellate cells", Liver Int, 28, pp.546~557 (2008)
  22. Paik YH, "Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats", Gut, 58, pp.1517~1527 (2009)
  23. Ruffels J, "Activation of ERK1", 2, JNK and PKB by hydrogen peroxide in human SH-SY5Y neuroblastoma cells : role of ERK1, Eur J Pharmacol, pp.2004, 483[DOI]
  24. Green DR, "Mitochondria and apoptosis", Science, 281, pp.1309~1312 (1998)
  25. Eberlein M, "Rho-dependent inhibition of the induction of connective tissue growth factor(CTGF)by HMG CoA reductase inhibitors(statins)", Br J Pharmacol, 133, pp.1172~1180 (2001)
  26. Patel R, "Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy", Circulation, 104, pp.317~324 (2001)
  27. Watts KL, "Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts", Am J Respir Cell Mol Biol, 32, pp.290~300 (2005)
  28. Latella G, "Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice", Liver Int, 29, pp.997~1009 (2009)
  29. Dooley S, "Hepatocyte-specific Smad7 expression attenuates TGF-beta-mediated fibrogenesis and protects against liver damage", Gastroenterology, 135, pp.642~659 (2008)
  30. Lo RC, "Histopathological evaluation of liver fibrosis and cirrhosis regression", Clin Mol Hepatol, 23, pp.302~307 (2017)
  31. Murphy FR, "Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition : implications for reversibility of liver fibrosis", J Biol Chem, 277, pp.11069~11076 (2002)
  32. Miyaki T, "Pitavastatin inhibits hepatic steatosis and fibrosis in non-alcoholic steatohepatitis model rats", Hepatol Res, 41, pp.375~385 (2011)
  33. Xu L, "Human hepatic stellate cell lines, LX-1 and LX-2 : new tools for analysis of hepatic fibrosis", Gut, 54, pp.142~151 (2005)
  34. Ohyama T, "Transforming growth factor-α attenuates hepatic fibrosis : possible involvement of matrix metalloproteinase-1", Liver Int, 31, pp.572~584 (2011)
  35. Wataru Ando, "Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis", Clinical and Molecular Hepatology, 24(1), pp.61~76 (2018), 대한간학회
  36. Kossakowska AE, "Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis", Am J Pathol, 153, pp.1895~1902 (1998)

관련 논문AI추천

The Effects of Combined Treatment with an HMG-CoA Reductase Inhibitor and PPARγ Agonist on the Activation of Rat Pancreatic Stellate Cells김창덕, 서연석, 엄순호, 유호상, 이범재, 이홍식, 전훈재, 정성우, Jai Hyun Choi, Sang Woo Lee, Yong Sik Kim, Yoon Tae Jeen거트앤리버 소화기연관학회협의회 · Gut and Liver2012 · 제6권 제2호Peroxisome Proliferator-Activated Receptor Gamma Agonist Attenuates Liver Fibrosis by Several Fibrogenic Pathways in an Animal Model of Cholestatic FibrosisAntonius Hocky Pudjiadi, Fatima Safira Alatas, Stephanie Wijaya, Tomoaki Taguchi, Toshiharu Matsuura대한소아소화기영양학회 · Pediatric Gastroenterology, Hepatology & Nutrition2020 · 제23권 제4호Anti-fibrotic effects of Orostachys japonicus A. Berger (Crassulaceae) on hepatic stellate cells and thioacetamide-induced fibrosis in rats김진섭, 송민동, 신광모, 염문정, 이재동, 채윤진, 천치수, KOPPULA SUSHRUTA, Tony Yoon한국영양학회 · Nutrition Research and Practice2017 · 제11권 제6호대황과 실리마린의 병용투여의 간섬유화 보호 효과노성수, 정일하, 지상우대한한방내과학회 · 대한한방내과학회지2023 · 제44권 제3호Mest Attenuates CCl4-Induced Liver Fibrosis in Rats by Inhibiting the Wnt/ β-Catenin Signaling PathwayChuanlong Zhu, Quan Wu, Rentao Gao, Wenting Li, Yi Li거트앤리버 소화기연관학회협의회 · Gut and Liver2014 · 제8권 제3호Doxazosin Treatment Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Hamsters through a Decrease in Transforming Growth Factor β SecretionDaniel Cervantes-García, Edgar de Jesus Tavares-Rodríguez, Javier Ventura-Juárez, Luis Muñoz-Fernández, María del Rosario Campos-Esparza, Martin Gerardo-Rodríguez, Martin Humberto Muñoz-Ortega, Norma Isabel Romero-Delgadillo, Raúl Wiliberto Llamas-Ramírez, Tania Guadalupe Elías-Flores거트앤리버 소화기연관학회협의회 · Gut and Liver2016 · 제10권 제1호

이 간행물의 다른 논문 (20건)