A target role for mast cell in the prevention and therapy of hepatic fibrosis

https://doi.org/10.1016/j.mehy.2007.07.042Get rights and content

Summary

Hepatic fibrosis is a common pathological process of chronic hepatic disease. Despite the extensive studies, the pathophysiological mechanisms in hepatic fibrosis remain unclear. Mast cell has a variety of physiological and pathological functions through the production of heparin, histamine, neutrophil chemoattractants, immunoregulatory cytokines, and mast cell-specific serine proteases tryptase and chymase. The survival and proliferation of mast cell are dependent upon stem cell factor. More recently, the data have suggested that mast cell has been associated with hepatic fibrosis in many chronic liver diseases. However, to what extent the mast cell effects the hepatic fibrosis remains to be clarified. Several therapeutic approaches to inhibit mast cell activation have already demonstrated some clinical utility in tissue fibrosis or inflammatory diseases such as the use of mast cell stabilizers, inhibitors of tryptase or chymase, blockade of stem cell factor and anti-IgE therapy. The article introduces the hypothesis that mast cell has a central role when it is affected by its activation state in the progression of hepatic fibrosis, thus new therapeutic strategies for treatment of hepatic fibrosis are suggested by this hypothesis. Considering the important role of mast cell and the development of these tangible therapeutic approaches in hepatic fibrosis will enable us to target any types of chronic liver diseases, which appears to be a more reasonable or a promising strategy.

Introduction

Hepatic fibrosis is a very common disease in China and other countries, it is a wound-healing response to chronic liver injury, resulting from viral hepatitis, ethanol and drug abuse, which if persistent can lead to irreversible cirrhosis or liver failure [1]. Although liver fibrosis has been studied extensively, the underlying mechanisms involved in the development of essential hepatic fibrosis remain incomplete and drugs to prevent and treat fibrosis are only partially effective.

There is a widely accepted paradigm that activation of hepatic stellate cells (HSCs) leading to the accumulation of extracellular matrix (ECM) is the central event in liver fibrosis, and it is a widespread agreement that TGF-β up-regulation is an important factor responsible for various organ fibrosis [2]. Many studies have suggested that mast cells not only cause acute inflammation, but also have a role in the induction of chronic inflammation [3], and the involvement of mast cells in hepatic fibrosis has been reported [4], [5]. Indeed, mast cells are known to participate in the pathogenesis of hepatic fibrosis in many chronic liver disease. However, the mechanism involved in this phenomenon is still poorly understood, current therapies are ineffective or only marginally effective, and the precise role of mast cells in the process is unknown.

Mast cells contain a variety of biologically active compounds and mediators like proteoglycans, arachidonic acid derivates and different neutral proteases like carboxypeptidase, cathepsin G, tryptase and chymase [6]. The latter may be specific for mast cells, since tryptase is found only in basophils, in very small amounts [7], and chymase is exclusively produced by mast cells [8]. Furthermore, mast cells are able to synthesize a multitude of cytokines and growth factors, suggesting the involvement of these cells in various biological processes [9], [10], [11]. In this article, hypothesize that mast cell has a central role in the progression of hepatic fibrosis when it is affected by its activation state, in a way that could contribute to the progression of hepatic fibrosis.

Section snippets

Mast cell and hepatic fibrosis

Fibrosis can occur in any organ and is a major medical problem ranging from dysfunction to progressive disability and death. Hepatic fibrosis, which may ultimately lead to cirrhosis, is the pathological base of all the chronic hepatic diseases and is characterized by the net accumulation of ECM, including collagen, glycoproteins, and proteoglycans [12]. Mast cells are distributed in connective tissue and in the mucosal membrane of all organs [13]. Major inflammatory and profibrogenic mediators

Mast cell: a therapy target to hepatic fibrosis

Liver fibrogenesis represents the common response of the liver to toxic, infectious, or metabolic agents and is characterized by excessive accumulation of ECM caused by both increased synthesis and deposition of newly formed components, and decreased or unbalanced degradation of ECM [35], [36], ultimately leading to cirrhosis and many complications: portal hypertension, liver failure, and hepatocellular carcinoma. Both clarification of the molecular mechanisms underlying pathological fibrosis

Hypotheses

Although there are not currently effective treatments to retard the progression of hepatic fibrosis in chronic liver disease and the mast cells responses to the hepatic fibrosis progress are complex, the pathophysiological mechanisms during the fibrogenic response and the relationship between mast cells and hepatic fibrosis are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various mast cell stabilizing drugs,

References (38)

  • W.A. Border et al.

    Transforming growth factor beta in tissue fibrosis

    N Engl J Med

    (1994)
  • I.I. Stoyanova

    Relevance of mast cells and hepatic lobule innervation to liver injury

    Rom J Gastroenterol

    (2004)
  • M. Yamashiro et al.

    Distribution of intrahepatic mast cells in various hepatobiliary disorders. An immunohistochemical study

    Virchows Arch

    (1998)
  • L.B. Schwartz

    Tryptase from human mast cells:biochemistry, biology and clinical utility

    Monogr Allergy

    (1990)
  • N.M. Schechter

    Human chymase

    Monogr Allergy

    (1990)
  • C.K. Oh et al.

    Transcriptional regulation of the TCA3 gene in mast cells after Fc epsilon RI cross-linking

    J Immunol

    (1994)
  • R. Alam et al.

    Macrophage inflammatory protein-1 alpha and monocyte chemoattractant peptide-1 elicit immediate and late cutaneous reactions and activate murine mast cells in vivo

    J Immunol

    (1994)
  • T.J. Smith et al.

    Preferential expression of interleukin-12 or interleukin-4 by murine bone marrow mast cells derived in mast cell growth factor or interleukin-3

    Eur J Immunol

    (1994)
  • P. Liu et al.

    Effects of Fuzheng Huayu 319 recipe on liver fibrosis in chronic hepatitis B

    World J Gastroenterol

    (1998)
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