BMC Complementary and Alternative Medicine | |
Paeoniflorin regulates macrophage activation in dimethylnitrosamine-induced liver fibrosis in rats | |
Lingqing Lu3  Qi Pan2  Qingnian Xu2  Zhen Lv3  Zongguo Yang3  Yunfei Lu2  Cheng Liu1  Xiaorong Chen2  | |
[1] Scientific Research Center, Shanghai Public Health Clinical Center, Shanghai, 201508, China;Key Laboratory of Infectious Diseases of State Administration of Traditional Chinese Medicine (clinical base), Shanghai, 201508, China;Department of Traditional Chinese Medicine, Shanghai Public Health Clinical Center, 2901 Caolang Road, Jin Shan District, Shanghai, 201508, China | |
关键词: Paeoniflorin; Macrophage; Liver fibrosis; | |
Others : 1231371 DOI : 10.1186/1472-6882-12-254 |
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received in 2012-04-01, accepted in 2012-12-05, 发布年份 2012 | |
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【 摘 要 】
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 3rd 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.
【 授权许可】
2012 Chen et al.; licensee BioMed Central Ltd.
【 预 览 】
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【 参考文献 】
- [1]Munshi MK, Uddin MN, Glaser SS: The role of the renin-angiotensin system in liver fibrosis. Exp Biol Med 2011, 236:557-566.
- [2]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.
- [3]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.
- [4]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.
- [5]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.
- [6]Gehring S, Dickson EM, San Martin ME, van Rooijen N, Papa EF, Harty MW, Tracy TF Jr, Gregory SH: Kupffer cells abrogate cholestatic liver injury in mice. Gastroenterology 2006, 130:810-822.
- [7]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.
- [8]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.
- [9]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]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.
- [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.
- [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.
- [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.
- [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.
- [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.
- [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.
- [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.
- [18]Scheuer PJ: Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991, 13:372-374.
- [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.
- [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.
- [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.
- [22]Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 2005, 115:209-218.
- [23]Friedman SL: Mechanisms of hepatic fibrogenesis. Gastroenterology 2008, 134:1655-1669.
- [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.
- [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.
- [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.
- [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.
- [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.
- [29]Wilkinson J, Radkowski M, Eschbacher JM, Laskus T: Activation of brain macrophages/microglia cells in hepatitis C infection. Gut 2010, 59:1394-1400.
- [30]Bannenberg G, Lundborg M, Johansson A: Pulmonary macrophage function in systemic gadolinium chloride-pretreated rats. Toxicol Lett 1995, 80:105-107.
- [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.
- [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.
- [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.
- [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.