A target role for mast cell in the prevention and therapy of hepatic fibrosis
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,
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2018, Archives of Medical ResearchHistamine induces NF-κB controlled cytokine secretion by orbital fibroblasts via histamine receptor type-1
2016, Experimental Eye ResearchCitation Excerpt :Histamine is a biogenic amine that is highly expressed in granules of mast cells and released upon their activation and which causes vasodilation, bronchoconstriction, increased capillary permeability, and smooth muscle contraction, all phenomena commonly associated with allergic and inflammatory reactions (da Silva et al., 2014). Moreover, histamine has been found to induce chemotaxis, proliferation, extracellular matrix molecule and inflammatory mediator synthesis by fibroblasts, thereby contributing to wound healing and tissue remodeling but also fibrosis (Abe et al., 2002; Dommisch et al., 2015; Franceschini et al., 2006; Garbuzenko et al., 2002, 2004; Holdsworth and Summers, 2008; Hong et al., 2015; Horie et al., 2014; Kunzmann et al., 2007; Li et al., 2007; Rankin et al., 1987; Shen, 2008; Veerappan et al., 2013; Walls et al., 1991; Wulff et al., 2012; Yang et al., 2014). Histamine effects can be mediated through four types of G-protein coupled histamine receptors; HRH1 to HRH4 (Jutel et al., 2009) but differences in specific histamine receptor involvement may exist between fibroblasts from different anatomical regions (Horie et al., 2014; Zeng et al., 2014).
Tryptase inhibitor APC 366 prevents hepatic fibrosis by inhibiting collagen synthesis induced by tryptase/protease-activated receptor 2 interactions in hepatic stellate cells
2014, International ImmunopharmacologyCitation Excerpt :Hepatic fibrosis is a common chronic liver disease consequent to wound-healing responses to various hepatic injuries, which if persistent can lead to irreversible cirrhosis or liver failure [1]. Although liver fibrosis has been studied extensively, the underlying mechanisms remain incompletely understood and drugs to prevent and treat fibrosis are only partially effective [2]. Previous studies have shown that mast cells not only induce acute inflammation, but also have a role in the induction of chronic inflammation [3].
Protease-activated receptor-2 modulates hepatic stellate cell collagen release and apoptotic status
2014, Archives of Biochemistry and BiophysicsCitation Excerpt :Koruk et al. indicate increases in liver mast cells in patients with chronic hepatitis C [16]. Shen indicates that mast cell has been associated with hepatic fibrosis in many chronic liver diseases, and proposes that a target role for mast cell in the prevention and therapy of hepatic fibrosis [17]. One of the major pathologic changes of hepatic fibrosis is the excessive accumulation of the extracellular matrix in the liver.
Preservation of basal AcSDKP attenuates carbon tetrachloride-induced fibrosis in the rat liver
2010, Journal of HepatologyCitation Excerpt :This is not unexpected since increased ACE occurs in CCl4-induced liver fibrosis and may cause excessive AcSDKP degradation [23]. These results suggest that liver fibrosis in other animal models or humans, which are associated with increased mast cells, oxidative stress, and ACE activity, may also have decreased local AcSDKP [23,24]. Collectively, our results indicate that decreased AcSDKP in liver fibrosis may be mainly due to decreased release by POP and accelerated degradation by ACE.
Splanchnic Th<inf>2</inf> and Th<inf>1</inf> cytokine redistribution in microsurgical cholestatic rats
2010, Journal of Surgical ResearchCitation Excerpt :The increased hepatic sensibility to LPS is also maintained [7, 55], but with low responsiveness of the inflammatory cells, related to a decreased free radical production and phagocytic activity of these cells [56]. Liver mucosal mast cell hyperplasia and degranulation, with the release of profibrogenic mediators, correlate in this evolutive phase of extrahepatic cholestasis in the rat with the time of most active collagen synthesis [34, 57]. In later evolutive phases (6 wk), the sustained cholestatic injury induces micronodular cirrhosis.