Journal List > Korean J Gastroenterol > v.66(6) > 1007451

TOOLS
Korean J Gastroenterol. 2015 Dec;66(6):320-324. Korean.
Published online December 22, 2015.  https://doi.org/10.4166/kjg.2015.66.6.320
Copyright © 2015 The Korean Society of Gastroenterology
Inflammation and Hepatic Fibrosis, Then Hepatocellular Carcinoma
Oh Sang Kwon, Seong Han Choi and Ju Hyun Kim
Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University School of Medicine, Incheon, Korea.

Correspondence to: Ju Hyun Kim. Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdong-daero 774beon-gil, Namdong-gu, Incheon 21565, Korea. Tel: +82-32-460-3778, Fax: +82-32-460-3408, Email: jhkim@gilhospital.com

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Abstract

Inflammation is one of the most prominent characteristic features of chronic liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most of HCC cases develop in patients with cirrhosis and cirrhosis develops in patients with chronic liver inflammation. Therefore, there is no doubt that there exist some strong connection among inflammation, fibrosis, and cancer. In fact, chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. This review will discuss the common mechanism of inflammation and fibrosis in chronic liver diseases, and then demonstrate why HCC develops in inflammatory and fibrotic conditions.

Keywords: Inflammation; Fibrosis; Cirrhosis; Hepatocellular carcinoma

Figures


 Fig. 1
LPS-TLRs signaling induce liver injury and fibrogenesis. In chronic liver disease, gut permeability is increased. This situation increases the likelihood of bacterial translocation and permeability of LPS. PAMPs including LPS freely travel through portal vein and arrive at the liver. LPS attach to TLRs and then activate hepatic stellate cell and Kupffer cell, which induce inflammation and fibrosis. LPS, lipopolysccharide; TLRs, toll-like receptors, PAMPs; pathogen-associated molecular patterns.
Click for larger image


Fig. 2
Cell death by inflammation induces fibrosis. Cell death molecules including apoptotic bodies are engulfed and digested by HSC and Kupffer cell. This situation activated HSC and then produce excessive extracellular matrix including collagen. HSC, hepatic stellate cell; ROS, reactive oxygen species.
Click for larger image

Notes

Financial support:None.

Conflict of interest:None.

References
1. Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2015;61:1066–1079.
2. Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 2014;147:765–783.e764.
3. Pradere JP, Kluwe J, De Minicis S, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 2013;58:1461–1473.
4. Wynn TA, Barron L. Macrophages: master regulators of inflammation and fibrosis. Semin Liver Dis 2010;30:245–257.
5. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209–218.
6. Friedman SL, Arthur MJ. Activation of cultured rat hepatic lipocytes by Kupffer cell conditioned medium. Direct enhancement of matrix synthesis and stimulation of cell proliferation via induction of platelet-derived growth factor receptors. J Clin Invest 1989;84:1780–1785.
7. Melhem A, Muhanna N, Bishara A, et al. Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC. J Hepatol 2006;45:60–71.
8. Jeong WI, Park O, Suh YG, et al. Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. Hepatology 2011;53:1342–1351.
9. Seki E, De Minicis S, Osterreicher CH, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat Med 2007;13:1324–1332.
10. Pradere JP, Troeger JS, Dapito DH, Mencin AA, Schwabe RF. Toll-like receptor 4 and hepatic fibrogenesis. Semin Liver Dis 2010;30:232–244.
11. Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev Immunol 2008;8:279–289.
12. Beutler B. Neo-ligands for innate immune receptors and the etiology of sterile inflammatory disease. Immunol Rev 2007;220:113–128.
13. Lotze MT, Zeh HJ, Rubartelli A, et al. The grateful dead: damage-associated molecular pattern molecules and reduction/oxidation regulate immunity. Immunol Rev 2007;220:60–81.
14. Su GL, Klein RD, Aminlari A, et al. Kupffer cell activation by lipopolysaccharide in rats: role for lipopolysaccharide binding protein and toll-like receptor 4. Hepatology 2000;31:932–936.
15. Matsumura T, Degawa T, Takii T, et al. TRAF6-NF-kappaB pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes. Immunology 2003;109:127–136.
16. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in cirrhosis. Hepatology 2005;41:422–433.
17. Wells CL, Maddaus MA, Reynolds CM, Jechorek RP, Simmons RL. Role of anaerobic flora in the translocation of aerobic and facultatively anaerobic intestinal bacteria. Infect Immun 1987;55:2689–2694.
18. Lin RS, Lee FY, Lee SD, et al. Endotoxemia in patients with chronic liver diseases: relationship to severity of liver diseases, presence of esophageal varices, and hyperdynamic circulation. J Hepatol 1995;22:165–172.
19. Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in cirrhosis. Semin Liver Dis 2008;28:26–42.
20. Bjarnason I, Peters TJ, Wise RJ. The leaky gut of alcoholism: possible route of entry for toxic compounds. Lancet 1984;1:179–182.
21. Draper LR, Gyure LA, Hall JG, Robertson D. Effect of alcohol on the integrity of the intestinal epithelium. Gut 1983;24:399–404.
22. Nanji AA, Tahan SR, Wei Y, Sadrzadeh SM. Hepatic sinusoidal endothelial cell G1/S arrest correlates with severity of alcoholic liver injury in the rat. Gastroenterology 1994;107:818–823.
23. Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 1995;108:218–224.
24. Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG. Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 2001;34:101–108.
25. Hansen J, Cherwitz DL, Allen JI. The role of tumor necrosis factor-alpha in acute endotoxin-induced hepatotoxicity in ethanol-fed rats. Hepatology 1994;20:461–474.
26. Cani PD, Bibiloni R, Knauf C, et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–1481.
27. Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest 2003;83:655–663.
28. Martinon F, Mayor A, Tschopp J. The inflammasomes: guardians of the body. Annu Rev Immunol 2009;27:229–265.
29. Watanabe A, Sohail MA, Gomes DA, et al. Inflammasome-mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2009;296:G1248–G1257.
30. Martin H, Sarsat JP, Lerche-Langrand C, et al. Morphological and biochemical integrity of human liver slices in long-term culture: effects of oxygen tension. Cell Biol Toxicol 2002;18:73–85.
31. Rosmorduc O, Housset C. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. Semin Liver Dis 2010;30:258–270.
32. Yoshiji H, Kuriyama S, Yoshii J, et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 2003;52:1347–1354.
33. Novo E, Cannito S, Zamara E, et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 2007;170:1942–1953.
34. Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011;8:108–118.
35. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88:125–172.
36. Kang N, Gores GJ, Shah VH. Hepatic stellate cells: partners in crime for liver metastases? Hepatology 2011;54:707–713.
37. Santamato A, Fransvea E, Dituri F, et al. Hepatic stellate cells stimulate HCC cell migration via laminin-5 production. Clin Sci (Lond) 2011;121:159–168.
38. Dapito DH, Mencin A, Gwak GY, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012;21:504–516.
39. Coulouarn C, Clément B. Stellate cells and the development of liver cancer: therapeutic potential of targeting the stroma. J Hepatol 2014;60:1306–1309.
40. Coulouarn C, Corlu A, Glaise D, Guénon I, Thorgeirsson SS, Clément B. Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res 2012;72:2533–2542.
41. Mikula M, Proell V, Fischer AN, Mikulits W. Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion. J Cell Physiol 2006;209:560–567.
42. Shin SK, Kim JH, Park H, et al. Improvement of liver function and non-invasive fibrosis markers in hepatitis B virus-associated cirrhosis: 2 years of entecavir treatment. J Gastroenterol Hepatol. 2015 [doi: 10.1111/jgh.13020]
[Epub ahead of print].
43. Hosaka T, Suzuki F, Kobayashi M, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 2013;58:98–107.
44. Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B. Aliment Pharmacol Ther 2013;38:98–106.
TOOLS
Similar articles

Hepatic Fibrosis and Cancer: The Silent Threats of Metabolic Syndrome

Efficacy of Hepatic Arterial Infusion Chemotherapy and Radiofrequency Ablation against Hepatocellular Carcinoma Refractory to Transarterial Chemoembolization and Vascular Variation: A Case Study

A single hepatic mass with two tales: hepatic tuberculosis and hepatocellular carcinoma

Clinical application of liver stiffness measurement for assessing the risk of hepatocellular carcinoma

Rapid Intra-Hepatic Dissemination of Hepatocellular Carcinoma with Pulmonary Metastases Following Combined Loco-Regional Therapy