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The Complex Functions of Mast Cells in Chronic Human Liver Diseases

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Abstract

Mast cells (MCs) are multifunctional effector cells of the immune system. MCs were originally thought to be involved in IgE-associated immediate hypersensitivity and allergic disorders, but it is now known that they contain or elaborate an array of mediators with a multitude of effects on many other cells. A number of studies have found that MCs are involved in various liver diseases. Although still controversial, they seem to be involved in the liver’s fibrotic response to chronic inflammation and parasitic infection. Hepatic fibrosis is the most frequent liver response to toxic, infectious, or metabolic agents. During the establishment of this pathological condition, there is an increase in the components of the basement membrane that leads to continuous basement membrane-like structures being raised within Disse’s space and a decrease in the number of sinusoid endothelial fenestrae. This leads to a complex process called “sinusoidal capillarization.” At the cellular level, liver fibrogenesis is initiated by hepatocyte necrosis, which induces the recruitment of a large number of inflammatory cells, including MCs, which can be considered the primary effectors of the process changing sinusoidal endothelial cells into capillary-type endothelial cells. We review the roles played by MCs in hepatic chronic diseases and describe a biopsy section of hepatic tissue taken from a patient with chronic C virus-related hepatitis showing diffuse sinusoidal capillarization and a high density of MCs. This observation has led us to hypothesize a relationship between these highly specialized cells and sinusoidal capillarization.

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References

  1. Ehrlich P (1878) Beitrage zur theorie und praxis der histologischen farbung. Thesis. Leipzig University, Leipzig

    Google Scholar 

  2. Schwartz LB (1985) The mast cells. In: Kaplan AP (ed). Allergy, vol I. Churchill Livingstone, Edinburgh, pp 53–92

    Google Scholar 

  3. Galli SJ (1990) New insights into “the riddle of the mast cells”: microenvironmental regulation of mast cell development and phenotypic heterogeneity. Lab Invest 62:5–33

    CAS  PubMed  Google Scholar 

  4. Burnet FM (1977) The probable relationship of some or all mast cells to the T-cell system. Cell Immunol 30:358–360

    Article  CAS  PubMed  Google Scholar 

  5. Zucker-Franklin D, Grusky G, Hirayama N, Schnipper E (1981) The presence of mast cell precursors in rat peripheral blood. Blood 58:544–551

    CAS  PubMed  Google Scholar 

  6. Welle M (1997) Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase. J Leukoc Biol 61:233–245

    CAS  PubMed  Google Scholar 

  7. Hatanaka K, Kitamura Y, Nishimune Y (1979) Local development of mast cells from bone marrow-derived precursors in the skin of mice. Blood 53:142–147

    CAS  PubMed  Google Scholar 

  8. Hayashi C, Sonoda T, Nakano T, Nakayama H, Kitamura Y (1985) Mast-cell precursors in the skin of mouse embryos and their deficiency in embryos of Sl/Sld genotype. Dev Biol 109:234–241

    Article  CAS  PubMed  Google Scholar 

  9. Kitamura Y, Fujita J (1989) Regulation of mast cell differentiation. Bioessays 10:193–196

    Article  CAS  PubMed  Google Scholar 

  10. Krishnaswamy G, Kelley J, Johnson D, Youngberg G, Stone W, Huang SK, Bieber J, Chi DS (2001) The human mast cell: functions in physiology and disease. Front Biosci 6:D1109–D1127

    CAS  PubMed  Google Scholar 

  11. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M (2005) Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23:749–286

    Article  CAS  PubMed  Google Scholar 

  12. Strobel S, Miller HR, Ferguson A (1981) Human intestinal mucosal mast cells: evaluation of fixation and staining techniques. J Clin Pathol 34:851–858

    CAS  PubMed  Google Scholar 

  13. Irani AM, Schwartz LB (1994) Human mast cell heterogeneity. Allergy Proc 15:303–308

    Article  CAS  PubMed  Google Scholar 

  14. Marone G, Lichtenstein LM, Galli SJ (2000) Mast cells and basophils. Academic Press, New York

    Google Scholar 

  15. Castells MC, Irani AM, Schwartz LB (1987) Evaluation of human peripheral blood leukocytes for mast cell tryptase. J Immunol 138:2184–2189

    CAS  PubMed  Google Scholar 

  16. Weidner N, Austen KF (1993) Heterogeneity of mast cells at multiple body sites. Fluorescent determination of avidin binding and immunofluorescent determination of chymase, tryptase, and carboxypeptidase content. Pathol Res Pract 189:156–162

    CAS  PubMed  Google Scholar 

  17. Bradding P (1996) Human mast cell cytokines. Clin Exp Allergy 26:13–19

    Article  CAS  PubMed  Google Scholar 

  18. Kruger-Krasagakes S, Czarnetzki BM (1995) Cytokine secretion by human mast cells. Exp Dermatol 4:250–254

    Article  CAS  PubMed  Google Scholar 

  19. Gruber BL (2003) Mast cells in the pathogenesis of fibrosis. Curr Rheumatol Rep 5:147–153

    PubMed  Google Scholar 

  20. Kawakami T, Galli SJ (2002) Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol 2:773–786

    Article  CAS  PubMed  Google Scholar 

  21. Payne V, Kam PC (2004) Mast cell tryptase: a review of its physiology and clinical significance. Anaesthesia 59:695–703

    Article  CAS  PubMed  Google Scholar 

  22. Mihm MC Jr, Soter NA, Dvorak HF, Austen KF (1976) The structure of normal skin and the morphology of atopic eczema. J Invest Dermatol 67:305–312

    Article  PubMed  Google Scholar 

  23. Persinger MA, Lepage P, Simard JP, Parker GH (1983) Mast cell numbers in incisional wounds in rat skin as a function of distance, time and treatment. Br J Dermatol 108:179–187

    Article  CAS  PubMed  Google Scholar 

  24. Grizzi F, Franceschini B, Chiriva-Internati M, Liu Y, Hermonat PL, Dioguardi N (2003) Mast cells and human hepatocellular carcinoma. World J Gastroenterol 9:1469–1473

    CAS  PubMed  Google Scholar 

  25. Weiler-Norman C, Rehermann B (2004) The liver as an immunological organ. J Gastro Hepatol 19:5279–5283

    Article  Google Scholar 

  26. Murata K, Okudaira M, Akashio K (1973) Mast cells in human liver tissue. Increased mast cell number in relation to the components of connective tissue in the cirrhotic process. Acta Derm Venereol Suppl (Stockh) 73:157–165

    CAS  Google Scholar 

  27. Hagmann W, Hacker HJ, Buchholz U (1992) Resident mast cells are the main initiators of anaphylactic leukotriene production in the liver. Hepatology 16:1477–1484

    CAS  PubMed  Google Scholar 

  28. Bardadin KA, Scheuer PJ (1986) Mast cells in acute hepatitis. J Pathol 149:315–325

    Article  CAS  PubMed  Google Scholar 

  29. Farrell DJ, Hines JE, Walls AF, Kelly PJ, Bennett MK, Burt AD (1995) Intrahepatic mast cells in chronic liver diseases. Hepatology 22:1175–1181

    Article  CAS  PubMed  Google Scholar 

  30. Armbrust T, Batusic D, Ringe B, Ramadori G (1997) Mast cell distribution in human liver disease and experimental rat liver fibrosis. Indications for mast cell participation in development of liver fibrosis. J Hepatol 26:1042–1054

    Article  CAS  PubMed  Google Scholar 

  31. Rioux KP, Sharkey KA, Wallace JL, Swain MG (1996) Hepatic mucosal mast cell hyperplasia in rats with secondary biliary cirrhosis. Hepatology 23:888–895

    Article  CAS  PubMed  Google Scholar 

  32. Gittlen SD, Schulman ES, Maddrey WC (1990) Raised histamine concentrations in chronic cholestatic liver disease. Gut 31:96–99

    CAS  PubMed  Google Scholar 

  33. Umezu K, Yuasa S, Ichikawa A (1986) Inhibitory mechanism of tritoqualine on histamine release from mast cells. Biochem Pharmacol 35:3137–3142

    Article  CAS  PubMed  Google Scholar 

  34. Peng RY, Wang DW, Xu ZH, Gao YB, Yang RB, Liu P, Wang ZP, Li YP (1994) The changes and significance of mast cells in irradiated rat liver. J Environ Pathol Toxicol Oncol 13:111–116

    CAS  PubMed  Google Scholar 

  35. Nakamura A, Yamazaki K, Suzuki K, Sato S (1997) Increased portal tract infiltration of mast cells and eosinophils in primary biliary cirrhosis. Am J Gastroenterol 92:2245–2249

    CAS  PubMed  Google Scholar 

  36. Okazaki T, Hirota S, Xu ZD, Maeyama K, Nakama A, Kawano S, Hori M, Kitamura Y (1998) Increase of mast cells in the liver and lung may be associated with but not a cause of fibrosis: demonstration using mast cell-deficient Ws/Ws rats. Lab Invest 78:1431–1438

    CAS  PubMed  Google Scholar 

  37. Sugihara A, Tsujimura T, Fujita Y, Nakata Y, Terada N (1999) Evaluation of role of mast cells in the development of liver fibrosis using mast cell-deficient rats and mice. J Hepatol 30:859–867

    Article  CAS  PubMed  Google Scholar 

  38. Satomura K, Shimizu S, Nagato T, Komeichi H, Osuga M, Katsuta Y, Aramaki T, Omoto Y (2002) Establishment of an assay method for human mast cell chymase. Hepatol Res 24:361–367

    Article  CAS  PubMed  Google Scholar 

  39. Cairns JA, Walls AF (1997) Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest 99:1313–1321

    CAS  PubMed  Google Scholar 

  40. Gruber BL, Kew RR, Jelaska A, Marchese MJ, Garlick J, Ren S, Schwartz LB, Korn JH (1997) Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis. J Immunol 158:2310–2317

    CAS  PubMed  Google Scholar 

  41. Thompson HL, Burbelo PD, Gabriel G, Yamada Y, Metcalfe DD (1991) Murine mast cells synthesize basement membrane components. A potential role in early fibrosis. J Clin Invest 87:619–623

    CAS  Google Scholar 

  42. Galli SJ, Zsebo KM, Geissler EN (1994) The kit ligand, stem cell factor. Adv Immunol 55:1–96

    Article  CAS  PubMed  Google Scholar 

  43. Benyon RC (1999) Mast cells in the liver. Clin Exp Allergy 29:155–158

    Article  CAS  PubMed  Google Scholar 

  44. Gruber BL, Marchese MJ, Kew RR (1994) Transforming growth factor-beta 1 mediates mast cell chemotaxis. J Immunol 152:5860–5867

    CAS  PubMed  Google Scholar 

  45. Brito JM, Borojevic R (1997) Liver granulomas in schistosomiasis: mast cell-dependent induction of SCF expression in hepatic stellate cells is mediated by TNF-alpha. J Leukoc Biol 62:389–396

    CAS  PubMed  Google Scholar 

  46. Terada T, Matsunaga Y (2000) Increased mast cells in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Hepatol 33:961–966

    Article  CAS  PubMed  Google Scholar 

  47. Makhlouf HR, Ishak KG (2002) Sclerosed hemangioma and sclerosing cavernous hemangioma of the liver: a comparative clinicopathologic and immunohistochemical study with emphasis on the role of mast cells in their histogenesis. Liver 22:70–78

    Article  PubMed  Google Scholar 

  48. Tsuneyama K, Kono N, Yamashiro M, Kouda W, Sabit A, Sasaki M, Nakanuma Y (1999) Aberrant expression of stem cell factor on biliary epithelial cells and peribiliary infiltration of c-kit-expressing mast cells in hepatolithiasis and primary sclerosing cholangitis: a possible contribution to bile duct fibrosis. J Pathol 189:609–614

    Article  CAS  PubMed  Google Scholar 

  49. Satomura K, Yin M, Shimizu S, Kato Y, Nagano T, Komeichi H, Ohsuga M, Katsuta Y, Aramaki T, Omoto Y (2003) Increased chymase in livers with autoimmune disease: colocalization with fibrosis. J Nippon Med Sch 70:490–495

    Article  CAS  PubMed  Google Scholar 

  50. Ozaki S, Sato Y, Yasoshima M, Harada K, Nakanuma Y (2005) Diffuse expression of heparan sulfate proteoglycan and connective tissue growth factor in fibrous septa with many mast cells relate to unresolving hepatic fibrosis of congenital hepatic fibrosis. Liver Int 25:817–828

    Article  CAS  PubMed  Google Scholar 

  51. O’Keeffe C, Baird AW, Nolan N, McCormick PA (2002) Mast cell hyperplasia in chronic rejection after liver transplantation. Liver Transpl 8:50–57

    Article  PubMed  Google Scholar 

  52. Akin C, Metcalfe DD (2004) Systemic mastocytosis. Annu Rev Med 55:419–432

    Article  CAS  PubMed  Google Scholar 

  53. Neubauer K, Saile B, Ramadori G (2001) Liver fibrosis and altered matrix synthesis. Can J Gastroenterol 15:1871–1893

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. Mori T, Okanoue T, Sawa Y, Hori N, Ohta M, Kagawa K (1993) Defenestration of the sinusoidal endothelial cell in a rat model of cirrhosis. Hepatology 17:891–897

    Article  CAS  PubMed  Google Scholar 

  56. Neubauer K, Kruger M, Quondamatteo F, Knittel T, Saile B, Ramadori G (1999) Transforming growth factor-beta1 stimulates the synthesis of basement membrane proteins laminin, collagen type IV and entactin in rat liver sinusoidal endothelial cells. J Hepatol 31:692–702

    Article  CAS  PubMed  Google Scholar 

  57. Xu GF, Li PT, Wang XY, Jia X, Tian DL, Jiang LD, Yang JX (2004) Dynamic changes in the expression of matrix metalloproteinases and their inhibitors, TIMPs, during hepatic fibrosis induced by alcohol in rats. World J Gastroenterol 10:3621–3627

    CAS  PubMed  Google Scholar 

  58. Xu GF, Wang XY, Ge GL, Li PT, Jia X, Tian DL, Jiang LD, Yang JX (2004) Dynamic changes of capillarization and peri-sinusoid fibrosis in alcoholic liver diseases. World J Gastroenterol 10:238–243

    PubMed  Google Scholar 

  59. Zimmermann A, Zhao D, Reichen J (1999) Myofibroblasts in the cirrhotic rat liver reflect hepatic remodeling and correlate with fibrosis and sinusoidal capillarization. J Hepatol 30:646–652

    Article  CAS  PubMed  Google Scholar 

  60. Grizzi F, Franceschini B, Barbieri B, Gagliano N, Arosio B, Chiriva-Internati M, Annoni G, Dioguardi N (2002) Mast cell density: a quantitative index of acute liver inflammation. Anal Quant Cytol Histol 24:63–69

    PubMed  Google Scholar 

  61. Dioguardi N, Franceschini B, Aletti G, Russo C, Grizzi F (2003) Fractal dimension rectified meter for quantification of liver fibrosis and other irregular microscopic objects. Anal Quant Cytol Histol 25:312–320

    PubMed  Google Scholar 

  62. Grizzi F, Franceschini B, Gagliano N, Moscheni C, Annoni G, Vergani C, Hermonat PL, Chiriva-Internati M, Dioguardi N (2003) Mast cell density, hepatic stellate cell activation and TGF-beta1 transcripts in the aging Sprague-Dawley rat during early acute liver injury. Toxicol Pathol 31:173–178

    Article  CAS  PubMed  Google Scholar 

  63. Garovoy MR, Reddish MA, Rocklin RE (1983) Histamine-induced suppressor factor (HSF): inhibition of helper T cell generation and function. J Immunol 130:357–361

    CAS  PubMed  Google Scholar 

  64. Levi-Schaffer F, Pe’er J (2001) Mast cells and angiogenesis. Clin Exp Allergy 31:521–524

    Article  CAS  PubMed  Google Scholar 

  65. Kendall JC, Li XH, Galli SJ, Gordon JR (1997) Promotion of mouse fibroblast proliferation by IgE-dependent activation of mouse mast cells: role for mast cell tumor necrosis factor-alpha and transforming growth factor-beta 1. J Allergy Clin Immunol 99:113–123

    CAS  PubMed  Google Scholar 

  66. Grutzkau A, Kruger-Krasagakes S, Baumeister H, Schwarz C, Kogel H, Welker P, Lippert U, Henz BM, Moller A (1998) Synthesis, storage, and release of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by human mast cells: implications for the biological significance of VEGF. Mol Biol Cell 9:875–884

    CAS  PubMed  Google Scholar 

  67. Yamane A, Seetharam L, Yamaguchi S, Gotoh N, Takahashi T, Neufeld G, Shibuya M (1994) A new communication system between hepatocytes and sinusoidal endothelial cells in liver through vascular endothelial growth factor and Flt tyrosine kinase receptor family (Flt-1 and KDR/Flk-1). Oncogene 9:2683–2690

    CAS  PubMed  Google Scholar 

  68. Shibuya M (1995) Role of VEGF-flt receptor system in normal and tumor angiogenesis. Adv Cancer Res 67:281–316

    Article  CAS  PubMed  Google Scholar 

  69. Mochida S, Ishikawa K, Toshima K, Inao M, Ikeda H, Matsui A, Shibuya M, Fujiwara K (1998) The mechanisms of hepatic sinusoidal endothelial cell regeneration: a possible communication system associated with vascular endothelial growth factor in liver cells. J Gastroenterol Hepatol 13(Suppl):S1–S5

    CAS  PubMed  Google Scholar 

  70. Theoharides TC, Conti P (2004) Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol 25:235–241

    Article  CAS  PubMed  Google Scholar 

  71. Huang GW, Yang LY (2002) Metallothionein expression in hepatocellular carcinoma. World J Gastroenterol 8:650–653

    CAS  PubMed  Google Scholar 

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Acknowledgment

This paper has been supported by “Michele Rodriguez” Foundation – Institute for Quantitative Measures in Medicine, Milan, Italy.

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Correspondence to Fabio Grizzi.

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Franceschini, B., Ceva-Grimaldi, G., Russo, C. et al. The Complex Functions of Mast Cells in Chronic Human Liver Diseases. Dig Dis Sci 51, 2248–2256 (2006). https://doi.org/10.1007/s10620-006-9082-8

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