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BMC Complementary Medicine and Therapies

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Open Access 01-12-2012 | Research article

Paeoniflorin regulates macrophage activation in dimethylnitrosamine-induced liver fibrosis in rats

Authors: Xiaorong Chen, Cheng Liu, Yunfei Lu, Zongguo Yang, Zhen Lv, Qingnian Xu, Qi Pan, Lingqing Lu

Published in: BMC Complementary Medicine and Therapies | Issue 1/2012

Abstract

Background

Macrophages in other organs (e.g. kidneys, lungs, and spleen, et. al) have rarely been reported in the development of liver fibrosis. Therefore, it is important to investigate macrophage activation in the main organs in liver fibrosis. We investigated the potential antifibrogenic effects of paeoniflorin (PF) in a dimethylnitrosamine (DMN)-induced rat model with special focus on inhibiting macrophage activation in the main organs.

Methods

Rat hepatic fibrosis was induced by treatment with DMN three times weekly over a 4-week period. DMN rats were treated with water, PF, or gadolinium chloride (GdCl₃) from the beginning of the 3^rd week. The expression of CD68, marker of macrophage, was investigated using immunohistochemical, real-time PCR, and western blot analysis.

Results

Hepatic hydroxyproline content markedly decreased and histopathology improved in the DMN-PF rats. Expression of desmin and collagen 1 decreased notably in DMN-PF liver. CD68 expression in the liver, spleen and kidney increased markedly after 2 weeks but decreased in DMN-water rats. PF and GdCl₃ decreased CD68 expression in the liver and spleen and there was no effect on kidney. CD68 expression in the lung increased gradually during the course of DMN-induced liver fibrosis, and PF inhibited CD68 expression in the lung significantly while GdCl₃ increased CD68 markedly. Expression of tumor necrosis factor (TNF-α) was decreased significantly by GdCl₃ in the liver, as revealed by real-time PCR analysis. However, GdCl₃ could not decrease TNF-α level in the serum by enzyme linked immunosorbent assay (ELISA).

Conclusions

Macrophage activation was disrupted in the liver, spleen, lung and kidney during development of DMN-induced liver fibrosis. PF administration attenuated DMN-induced liver fibrosis at least in part by regulating macrophage disruption in the main organs.

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Munshi MK, Uddin MN, Glaser SS: The role of the renin-angiotensin system in liver fibrosis. Exp Biol Med. 2011, 236: 557-566. 10.1258/ebm.2011.010375.CrossRef

Liu C, Tao Q, Sun M, Wu JZ, Yang W, Jian P, Peng J, Hu Y, Liu C, Liu P: Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats. Lab Invest. 2010, 90: 1805-1816. 10.1038/labinvest.2010.123.CrossRefPubMed

Lee CM, Yeoh GC, Olynyk JK: Differential effects of gadolinium chloride on Kupffer cells in vivo and in vitro. Int J Biochem Cell Biol. 2004, 36: 481-488. 10.1016/j.biocel.2003.08.004.CrossRefPubMed

Thomas JA, Pope C, Wojtacha D, Robson AJ, Gordon-Walker TT, Hartland S, Ramachandran P, Van Deemter M, Hume DA, Iredale JP, Forbes SJ: Macrophage therapy for murine liver fibrosis recruits host effector cells improving fibrosis, regeneration, and function. Hepatology. 2011, 53: 2003-2015. 10.1002/hep.24315.CrossRefPubMed

Aoyama T, Inokuchi S, Brenner DA, Seki E: CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology. 2010, 52: 1390-1400. 10.1002/hep.23795.CrossRefPubMedPubMedCentral

Gehring S, Dickson EM, San Martin ME, van Rooijen N, Papa EF, Harty MW, Tracy TF, Gregory SH: Kupffer cells abrogate cholestatic liver injury in mice. Gastroenterology. 2006, 130: 810-822. 10.1053/j.gastro.2005.11.015.CrossRefPubMed

Akahoshi T, Hashizume M, Tanoue K, Shimabukuro R, Gotoh N, Tomikawa M, Sugimachi K: Role of the spleen in liver fibrosis in rats may be mediated by transforming growth factor beta-1. J Gastroenterol Hepatol. 2002, 17: 59-65. 10.1046/j.1440-1746.2002.02667.x.CrossRefPubMed

Kummer S, Sagir A, Pandey S, Feldkötter M, Habbig S, Körber F, Ney D, Hoppe B, Häussinger D, Mayatepek E, Oh J: Liver fibrosis in recessive multicystic kidney diseases: transient elastography for early detection. Pediatr Nephrol. 2011, 26: 725-731. 10.1007/s00467-011-1771-7.CrossRefPubMed

Chryssostalis A, Hubert D, Coste J, Kanaan R, Burgel PR, Desmazes-Dufeu N, Soubrane O, Dusser D, Sogni P: Liver disease in adult patients with cystic fibrosis: A frequent and independent prognostic factor associated with death or lung transplantation. J Hepatol. 2011, 55: 1377-1382. 10.1016/j.jhep.2011.03.028.CrossRefPubMed

10.

Xiao L, Wang YZ, Liu J, Luo XT, Ye Y, Zhu XZ: Effects of paeoniflorin on the cerebral infarction, behavioral and cognitive impairments at the chronic stage of transient middle cerebral artery occlusion in rats. Life Sci. 2005, 78: 413-420. 10.1016/j.lfs.2005.04.069.CrossRefPubMed

11.

Tsai HY, Lin YT, Chen CF, Tsai CH, Chen YF: Effects of veratrine and paeoniflorin on the isolated rat aorta. J Ethnopharmacol. 1999, 66: 249-255. 10.1016/S0378-8741(98)00236-0.CrossRefPubMed

12.

Wu H, Li W, Wang T, Shu Y, Liu P: Paeoniflorin suppress NF-kappaB activation through modulation of I kappaB alpha and enhances 5-fluorouracil-induced apoptosis in human gastric carcinoma cells. Biomed Pharmacother. 2008, 62: 659-666. 10.1016/j.biopha.2008.08.002.CrossRefPubMed

13.

Lee KK, Omiya Y, Yuzurihara M, Kase Y, Kobayashi H: Antinociceptive effect of paeoniflorin via spinal α(2)-adrenoceptor activation in diabetic mice. Eur J Pain. 2011, 15: 1035-1039. 10.1016/j.ejpain.2011.04.011.CrossRefPubMed

14.

Chu D, Du M, Hu X, Wu Q, Shen J: Paeoniflorin attenuates schistosomiasis japonica-associated liver fibrosis through inhibiting alternative activation of macrophages. Parasitology. 2011, 138: 1259-1271. 10.1017/S0031182011001065.CrossRefPubMed

15.

Ala-Kokko L, Pihlajaniemi T, Myers JC, Kivirikko KI, Savolainen ER: Gene expression of type III I and IV collagens in hepatic fibrosis induced by dimethylnitrosamine in the rat. Biochem J. 1987, 244: 75-79.CrossRefPubMedPubMedCentral

16.

Sakaida I, Hironaka K, Terai S, Okita K: Gadolinium chloride reverses dimethylnitrosamine (DMN)-induced rat liver fibrosis with increased matrix metalloproteinases (MMPs) of Kupffer cells. Life Sci. 2003, 72: 943-959. 10.1016/S0024-3205(02)02342-1.CrossRefPubMed

17.

Jamall IS, Finelli VN, Que Hee SS: A simple method to determine nanogram levels of 4-hydroyproline in biological tissues. Anal Biochem. 1981, 112: 70-75. 10.1016/0003-2697(81)90261-X.CrossRefPubMed

18.

Scheuer PJ: Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991, 13: 372-374. 10.1016/0168-8278(91)90084-O.CrossRefPubMed

19.

Angermayr B, Fernandez M, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J: NAD(P)H oxidase modulates angiogenesis and the development of portosystemic collaterals and splanchnic hyperaemia in portal hypertensive rats. Gut. 2007, 56: 560-564. 10.1136/gut.2005.088013.CrossRefPubMed

20.

Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP: Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005, 115: 56-65.CrossRefPubMedPubMedCentral

21.

Fallowfield JA, Mizuno M, Kendall TJ, Constandinou CM, Benyon RC, Duffield JS, Iredale JP: Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007, 178: 5288-5295.CrossRefPubMed

22.

Bataller R, Brenner DA: Liver fibrosis. J Clin Invest. 2005, 115: 209-218.CrossRefPubMedPubMedCentral

23.

Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008, 134: 1655-1669. 10.1053/j.gastro.2008.03.003.CrossRefPubMedPubMedCentral

24.

Zaldivar MM, Pauels K, von Hundelshausen P, Berres ML, Schmitz P, Bornemann J, Kowalska MA, Gassler N, Streetz KL, Weiskirchen R, Trautwein C, Weber C, Wasmuth HE: CXC chemokine ligand 4 (Cxcl4) is a platelet-derived mediator of experimental liver fibrosis. Hepatology. 2010, 51: 1345-1353. 10.1002/hep.23435.CrossRefPubMed

25.

Iredale JP: Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest. 2007, 117: 539-548. 10.1172/JCI30542.CrossRefPubMedPubMedCentral

26.

Albillos A, Nieto M, Ubeda M, Muñoz L, Fraile B, Reyes E, Lledó L, Blanco I, Pastor O, Salas C, Lario M, Monserrat J, Bataller R, Alvarez-Mon M: The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis. Gut. 2010, 59: 943-952. 10.1136/gut.2008.168831.CrossRefPubMed

27.

Hironaka K, Sakaida I, Matsumura Y, Kaino S, Miyamoto K, Okita K: Enhanced interstitial collagenase (matrix metalloproteinase-13) production of Kupffer cell by gadlinium chloride prevents pig serum-induced rat liver fibrosis in vivo. Biochem Biophys Res Commun. 2000, 267: 290-295. 10.1006/bbrc.1999.1910.CrossRefPubMed

28.

Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J: Effects of gadolinium chloride (GdCl3) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions. J Comp Pathol. 2005, 133: 92-102. 10.1016/j.jcpa.2005.01.011.CrossRefPubMed

29.

Wilkinson J, Radkowski M, Eschbacher JM, Laskus T: Activation of brain macrophages/microglia cells in hepatitis C infection. Gut. 2010, 59: 1394-1400. 10.1136/gut.2009.199356.CrossRefPubMed

30.

Bannenberg G, Lundborg M, Johansson A: Pulmonary macrophage function in systemic gadolinium chloride-pretreated rats. Toxicol Lett. 1995, 80: 105-107. 10.1016/0378-4274(95)03342-I.CrossRefPubMed

31.

Kono H, Fujii H, Amemiya H, Asakawa M, Hirai Y, Maki A, Tsuchiya M, Matsuda M, Yamamoto M: Role of Kupffer cells in lung injury in rats administered endotoxin. J Surg Res. 2005, 129: 176-189. 10.1016/j.jss.2005.06.009.CrossRefPubMed

32.

Kono H, Fujii H, Tsuchiya M, Hirai Y, Ishii K, Hosomura N, Tanaka N: Inhibition of the Kupffer cell and neutralization of IL-10 increase the expression of chemokines in the lung in a rat peritonitis model. J Surg Res. 2008, 150: 169-182. 10.1016/j.jss.2008.04.015.CrossRefPubMed

33.

Lomas-Neira J, Chung CS, Perl M, Gregory S, Biffl W, Ayala A: Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge. Am J Physiol Lung Cell Mol Physiol. 2006, 290: 51-58.CrossRef

34.

Kumagai K, Kiyosawa N, Ito K, Yamoto T, Teranishi M, Nakayama H, Manabe S: Influence of Kupffer cell inactivation on cycloheximide-induced hepatic injury. Toxicology. 2007, 241: 106-118. 10.1016/j.tox.2007.08.090.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/12/254/prepub

Title: Paeoniflorin regulates macrophage activation in dimethylnitrosamine-induced liver fibrosis in rats
Authors: Xiaorong Chen
Cheng Liu
Yunfei Lu
Zongguo Yang
Zhen Lv
Qingnian Xu
Qi Pan
Lingqing Lu
Publication date: 01-12-2012
Publisher: BioMed Central
Published in: BMC Complementary Medicine and Therapies / Issue 1/2012
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/1472-6882-12-254

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Springer Medicine

Paeoniflorin regulates macrophage activation in dimethylnitrosamine-induced liver fibrosis in rats

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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