Metformin suppresses intrahepatic coagulation activation in mice with lipopolysaccharide/D‑galactosamine‑induced fulminant hepatitis

Gong,Xianqiong; Duan,Rui; Ao,Jin‑E; Ai,Qing; Ge,Pu; Lin,Ling; Zhang,Li

doi:10.3892/mmr.2015.4206

Metformin suppresses intrahepatic coagulation activation in mice with lipopolysaccharide/D‑galactosamine‑induced fulminant hepatitis

Authors:
- Xianqiong Gong
- Rui Duan
- Jin‑E Ao
- Qing Ai
- Pu Ge
- Ling Lin
- Li Zhang
View Affiliations

Affiliations: Department of Liver Diseases, Hepatology Center, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian 361000, P.R. China, Department of General Surgery, The First People's Hospital of Jingmen, Jingmen, Hubei 448000, P.R. China, Department of Pathology, The First People's Hospital of Jingmen, Jingmen, Hubei 448000, P.R. China, Department of Physiology, Chongqing Medical University, Chongqing 400016, P.R. China, Department of Pathophysiology, Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: August 10, 2015 https://doi.org/10.3892/mmr.2015.4206
Pages: 6384-6390

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Metformin is a widely‑used antidiabetic drug with hypoglycemic activity and previously described anti‑inflammatory properties. Previous studies have demonstrated that metformin attenuates endotoxic hepatitis, however the mechanisms remain unclear. Inflammation and coagulation are closely associated pathological processes, therefore the potential effects of metformin on key steps in activation of the coagulation system were further investigated in endotoxic hepatitis induced by lipopolysaccharide/D‑galactosamine (LPS/D‑Gal). The current study demonstrated that treatment with metformin significantly suppressed the upregulation of tissue factor and plasminogen activator inhibitor‑1 in LPS/D‑Gal‑exposed mice. In addition, a reduction in the expression of interleukin 6 and inhibition of nuclear translocation of nuclear factor‑κB were observed. These data indicate that the LPS/D‑Gal‑induced elevation of the stable protein level of hypoxia inducible factor 1α, the mRNA level of erythropoietin, vascular endothelial growth factor and matrix metalloproteinase‑3, and the hepatic level of lactic acid were also suppressed by metformin. The current study indicates that the suppressive effects of metformin on inflammation‑induced coagulation may be an additional mechanism underlying the hepatoprotective effects of metformin in mice with LPS/D‑Gal‑induced fulminant hepatitis.

View Figures

View References

1	Schiødt FV and Lee WM: Fulminant liver disease. Clin Liver Dis. 7:331–349. vi2003. View Article : Google Scholar : PubMed/NCBI
2	Bernal W, Auzinger G, Dhawan A and Wendon J: Acute liver failure. Lancet. 376:190–201. 2010. View Article : Google Scholar : PubMed/NCBI
3	Tsutsui H, Adachi K, Seki E and Nakanishi K: Cytokine-induced inflammatory liver injuries. Curr Mol Med. 3:545–559. 2003. View Article : Google Scholar : PubMed/NCBI
4	Hatano E: Tumor necrosis factor signaling in hepatocyte apoptosis. J Gastroenterol Hepatol. 22(Suppl 1): S43–S44. 2007. View Article : Google Scholar : PubMed/NCBI
5	Kim SJ and Lee SM: NLRP3 inflammasome activation in D-galactosamine and lipopolysaccharide-induced acute liver failure: Role of heme oxygenase-1. Free Radic Biol Med. 65:997–1004. 2013. View Article : Google Scholar : PubMed/NCBI
6	Li Y, Xu Z, Yu Y, Yuan H, Xu H, Zhu Q, Wang C and Shi X: The vagus nerve attenuates fulminant hepatitis by activating the Src kinase in Kuppfer cells. Scand J Immunol. 79:105–112. 2014. View Article : Google Scholar
7	Levi M, Schultz M and van der Poll T: Sepsis and thrombosis. Semin Thromb Hemost. 39:559–566. 2013. View Article : Google Scholar : PubMed/NCBI
8	Aksu K, Donmez A and Keser G: Inflammation-induced thrombosis: Mechanisms, disease associations and management. Curr Pharm Des. 18:1478–1493. 2012. View Article : Google Scholar : PubMed/NCBI
9	Semeraro N, Ammollo CT, Semeraro F and Colucci M: Sepsis, thrombosis and organ dysfunction. Thromb Res. 129:290–295. 2012. View Article : Google Scholar
10	O'Brien M: The reciprocal relationship between inflammation and coagulation. Top Companion Anim Med. 27:46–52. 2012. View Article : Google Scholar : PubMed/NCBI
11	de Laforcade A: Diseases associated with thrombosis. Top Companion Anim Med. 27:59–64. 2012. View Article : Google Scholar : PubMed/NCBI
12	Gando S: Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med. 38(Suppl): S35–S42. 2010. View Article : Google Scholar : PubMed/NCBI
13	Egorina EM, Sovershaev MA and Hansen JB: The role of tissue factor in systemic inflammatory response syndrome. Blood Coagul Fibrinolysis. 22:451–456. 2011. View Article : Google Scholar : PubMed/NCBI
14	Mackman N: The many faces of tissue factor. J Thromb Haemost. 7(Suppl 1): 136–139. 2009. View Article : Google Scholar : PubMed/NCBI
15	Schouten M, Wiersinga WJ, Levi M and van der Poll T: Inflammation, endothelium, and coagulation in sepsis. J Leukoc Biol. 83:536–545. 2008. View Article : Google Scholar
16	Bergmann S and Hammerschmidt S: Fibrinolysis and host response in bacterial infections. Thromb Haemost. 98:512–520. 2007.PubMed/NCBI
17	Hermans PW and Hazelzet JA: Plasminogen activator inhibitor type 1 gene polymorphism and sepsis. Clin Infect Dis. 41(Suppl 7): S453–S458. 2005. View Article : Google Scholar : PubMed/NCBI
18	Yuan H, Li L, Zheng W, Wan J, Ge P, Li H and Zhang L: Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice. Int Immunopharmacol. 12:682–688. 2012. View Article : Google Scholar : PubMed/NCBI
19	Silverstein R: D-galactosamine lethality model: Scope and limitations. J Endotoxin Res. 10:147–162. 2004.PubMed/NCBI
20	Miyazaki M, Kato M, Tanaka M, Tanaka K, Takao S, Kohjima M, Ito T, Enjoji M, Nakamuta M, Kotoh K, et al: Antithrombin III injection via the portal vein suppresses liver damage. World J Gastroenterol. 18:1884–1891. 2012. View Article : Google Scholar : PubMed/NCBI
21	Takano H, Inoue K, Shimada A, Sato H, Yanagisawa R and Yoshikawa T: Urinary trypsin inhibitor protects against liver injury and coagulation pathway dysregulation induced by lipopolysaccharide/D-galactosamine in mice. Lab Invest. 89:833–839. 2009. View Article : Google Scholar : PubMed/NCBI
22	Kerr R, Stirling D and Ludlam CA: Interleukin 6 and haemostasis. Br J Haematol. 115:3–12. 2001. View Article : Google Scholar : PubMed/NCBI
23	Liang DY, Liu LM, Ye CG, Zhao L, Yu FP, Gao DY and Wang YY, Yang ZW and Wang YY: Inhibition of UII/UTR system relieves acute inflammation of liver through preventing activation of NF-κB pathway in ALF mice. PLoS One. 8:e648952014. View Article : Google Scholar
24	Jiang R, Wang NP, Tanaka KA, Levy JH, Guyton RA, Zhao ZQ and Vinten-Johansen J: Factor Xa induces tissue factor expression in endothelial cells by P44/42 MAPK and NF-κB-dependent pathways. J Surg Res. 169:319–327. 2011. View Article : Google Scholar
25	Rhim T, Lee DY and Lee M: Hypoxia as a target for tissue specific gene therapy. J Control Release. 172:484–494. 2013. View Article : Google Scholar : PubMed/NCBI
26	Ahn JK, Koh EM, Cha HS, Lee YS, Kim J, Bae EK and Ahn KS: Role of hypoxia-inducible factor-1alpha in hypoxia-induced expressions of IL-8, MMP-1 and MMP-3 in rheumatoid fibroblast-like synoviocytes. Rheumatology (Oxford). 47:834–839. 2008. View Article : Google Scholar
27	Bailey CJ and Turner RC: Metformin. N Engl J Med. 334:574–579. 1996. View Article : Google Scholar : PubMed/NCBI
28	Tsoyi K, Jang HJ, Nizamutdinova IT, Kim YM, Lee YS, Kim HJ, Seo HG, Lee JH and Chang KC: Metformin inhibits HMGB1 release in LPS-treated RAW 264.7 cells and increases survival rate of endotoxaemic mice. Br J Pharmacol. 162:1498–1508. 2011. View Article : Google Scholar :
29	Hattori Y, Suzuki K, Hattori S and Kasai K: Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells. Hypertension. 47:1183–1188. 2006. View Article : Google Scholar : PubMed/NCBI
30	Nath N, Khan M, Paintlia MK, Singh I, Hoda MN and Giri S: Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol. 182:8005–8014. 2009. View Article : Google Scholar : PubMed/NCBI
31	van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJ, Eerenberg AJ, de Groot ER, Jansen J, Gallati H, Büller HR, et al: Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med. 179:1253–1259. 1994. View Article : Google Scholar : PubMed/NCBI
32	Wyseure T and Declerck PJ: Novel or expanding current targets in fibrinolysis. Drug Discov Today. 19:1476–1482. 2014. View Article : Google Scholar : PubMed/NCBI
33	Dupont DM, Madsen JB, Kristensen T, Bodker JS, Blouse GE, Wind T and Andreasen PA: Biochemical properties of plasminogen activator inhibitor-1. Front Biosci (Landmark Ed). 14:1337–1361. 2009. View Article : Google Scholar
34	Kruithof EK: Regulation of plasminogen activator inhibitor type 1 gene expression by inflammatory mediators and statins. Thromb Haemost. 100:969–975. 2008.
35	Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar
36	Lee IT and Yang CM: Inflammatory signalings involved in airway and pulmonary diseases. Mediators Inflamm. 2013:7912312013. View Article : Google Scholar : PubMed/NCBI
37	Ong SG and Hausenloy DJ: Hypoxia-inducible factor as a therapeutic target for cardioprotection. Pharmacol Ther. 136:69–81. 2012. View Article : Google Scholar : PubMed/NCBI
38	Brocato J, Chervona Y and Costa M: Molecular responses to hypoxia-inducible factor 1α and beyond. Mol Pharmacol. 85:651–657. 2014. View Article : Google Scholar : PubMed/NCBI
39	Ramakrishnan P, Hecht BA, Pedersen DR, Lavery MR, Maynard J, Buckwalter JA and Martin JA: Oxidant conditioning protects cartilage from mechanically induced damage. J Orthop Res. 28:914–920. 2010. View Article : Google Scholar : PubMed/NCBI
40	Levy B: Lactate and shock state: The metabolic view. Curr Opin Crit Care. 12:315–321. 2006. View Article : Google Scholar : PubMed/NCBI
41	Soric S, Belanger MP, Askin N and Wittnich C: Impact of female sex hormones on liver tissue lactic acidosis during ischemia. Transplantation. 84:763–770. 2007. View Article : Google Scholar : PubMed/NCBI
42	James JH, Luchette FA, McCarter FD and Fischer JE: Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet. 354:505–508. 1999. View Article : Google Scholar : PubMed/NCBI