Effects of Enzymatically Depolymerized Low Molecular Weight Heparins on CCl-Induced Liver Fibrosis

Overview

Journal Front Pharmacol

Date 2017 Sep 6

PMID 28871223

Citations 6

Authors

Yishu Yan

Changge Guan

ShanShan Du

Wenming Zhu

Yang Ji

Nan Su

Xiang Mei

Dong He

Yuan Lu

Chong Zhang

Xin-Hui Xing

Affiliations

Soon will be listed here.

Abstract

With regard to identifying the effective components of LMWH drugs curing hepatic fibrosis disease, we carried out a comparative study on the efficacy of enzymatically depolymerized LMWHs on CCl induced mouse liver fibrosis. The results showed that the controlled enzymatic depolymerization conditions resulted in LMWHs with significantly different activities. The LMWH product depolymerized by Heparinase I (I-11) with a Mw of 7160, exhibited a significant advantage in reducing the liver inflammation by suppressing TNF-α and IL-1β secretion, and minimizing hepatic fibrogenesis. The products prepared by only Heparinase II (II-11), and combined Heparinase III and II (III-II-5) showed limited positive effect on hepatic inflammation and fibrosis. On the contrary, the products by combined Heparinase III and I (III-I-9, III-I-5) showed no effect or stimulation effect on the hepatic fibrogenesis. Our results provided the basis for structure-activity relationship insight for inhibition of liver fibrosis activities of LMWHs, which might have significant implications for generic anti-fibrosis disease drug development.

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References

Abe W, Ikejima K, Lang T, Okumura K, Enomoto N, Kitamura T . Low molecular weight heparin prevents hepatic fibrogenesis caused by carbon tetrachloride in the rat. J Hepatol. 2006; 46(2):286-94. DOI: 10.1016/j.jhep.2006.08.023. View

Rabenstein D . Heparin and heparan sulfate: structure and function. Nat Prod Rep. 2002; 19(3):312-31. DOI: 10.1039/b100916h. View

Mousavi S, Moradi M, Khorshidahmad T, Motamedi M . Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. Adv Pharmacol Sci. 2015; 2015:507151. PMC: 4443644. DOI: 10.1155/2015/507151. View

Fagone P, Mangano K, Pesce A, Portale T, Puleo S, Nicoletti F . Emerging therapeutic targets for the treatment of hepatic fibrosis. Drug Discov Today. 2015; 21(2):369-75. DOI: 10.1016/j.drudis.2015.10.015. View

Rockey D, Bell P, Hill J . Fibrosis--A Common Pathway to Organ Injury and Failure. N Engl J Med. 2015; 373(1):96. DOI: 10.1056/NEJMc1504848. View

Yan Y, Ji Y, Su N, Mei X, Wang Y, Du S . Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders: A review. Carbohydr Polym. 2017; 160:71-81. DOI: 10.1016/j.carbpol.2016.12.037. View

Satoh T, Nakagawa K, Sugihara F, Kuwahara R, Ashihara M, Yamane F . Identification of an atypical monocyte and committed progenitor involved in fibrosis. Nature. 2016; 541(7635):96-101. DOI: 10.1038/nature20611. View

Cerini F, Vilaseca M, Lafoz E, Garcia-Irigoyen O, Garcia-Caldero H, Tripathi D . Enoxaparin reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol. 2015; 64(4):834-42. DOI: 10.1016/j.jhep.2015.12.003. View

Calvaruso V, Maimone S, Gatt A, Tuddenham E, Thursz M, Pinzani M . Coagulation and fibrosis in chronic liver disease. Gut. 2008; 57(12):1722-7. DOI: 10.1136/gut.2008.150748. View

10.

Gunther A, Lubke N, Ermert M, Schermuly R, Weissmann N, Breithecker A . Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits. Am J Respir Crit Care Med. 2003; 168(11):1358-65. DOI: 10.1164/rccm.2201082. View

11.

Liu J, Tan H, Sun Y, Zhou S, Cao J, Wang F . The preventive effects of heparin-superoxide dismutase on carbon tetrachloride-induced acute liver failure and hepatic fibrosis in mice. Mol Cell Biochem. 2009; 327(1-2):219-28. DOI: 10.1007/s11010-009-0060-2. View

12.

Serisier D, Shute J, Hockey P, Higgins B, Conway J, Carroll M . Inhaled heparin in cystic fibrosis. Eur Respir J. 2006; 27(2):354-8. DOI: 10.1183/09031936.06.00069005. View

13.

Lee J, Lee H, Joung Y, Jung K, Choi J, Lee D . The use of low molecular weight heparin-pluronic nanogels to impede liver fibrosis by inhibition the TGF-β/Smad signaling pathway. Biomaterials. 2010; 32(5):1438-45. DOI: 10.1016/j.biomaterials.2010.10.023. View

14.

Fischer A, Jacobson K, Rose J, Zeller R . Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc. 2011; 2008:pdb.prot4986. DOI: 10.1101/pdb.prot4986. View

15.

Li J, Guo Z, Gao X, Bian Q, Jia M, Lai X . Low molecular weight heparin (LMWH) improves peritoneal function and inhibits peritoneal fibrosis possibly through suppression of HIF-1α, VEGF and TGF-β1. PLoS One. 2015; 10(2):e0118481. PMC: 4344343. DOI: 10.1371/journal.pone.0118481. View

16.

Jones C, Beni S, Limtiaco J, Langeslay D, Larive C . Heparin characterization: challenges and solutions. Annu Rev Anal Chem (Palo Alto Calif). 2011; 4:439-65. DOI: 10.1146/annurev-anchem-061010-113911. View

17.

Pradere J, Kluwe J, De Minicis S, Jiao J, Gwak G, Dapito D . Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology. 2013; 58(4):1461-73. PMC: 3848418. DOI: 10.1002/hep.26429. View

18.

Wu J, Zhang C, Mei X, Li Y, Xing X . Controllable production of low molecular weight heparins by combinations of heparinase I/II/III. Carbohydr Polym. 2013; 101:484-92. DOI: 10.1016/j.carbpol.2013.09.052. View

19.

Abdel-Salam O, Baiuomy A, Ameen A, Hassan N . A study of unfractionated and low molecular weight heparins in a model of cholestatic liver injury in the rat. Pharmacol Res. 2004; 51(1):59-67. DOI: 10.1016/j.phrs.2004.04.009. View

20.

Poelstra K . Liver fibrosis in 2015: Crucial steps towards an effective treatment. Nat Rev Gastroenterol Hepatol. 2016; 13(2):67-8. DOI: 10.1038/nrgastro.2015.224. View