Digestive and Liver Disease
Volume 42, Issue 8 , Pages 529-536, August 2010

A review of mast cells and liver disease: What have we learned?

  • Heather Francis

      Affiliations

    • Department of Internal Medicine, College of Medicine, Texas A&M Health Science Center, Temple, TX, United States
    • Department of Research and Education, Scott & White Hospital, College of Medicine, Texas A&M Health Science Center, Temple, TX, United States
    • Systems Biology and Translational Medicine, College of Medicine, Texas A&M Health Science Center, Temple, TX, United States
    • Corresponding Author InformationCorresponding author at: Texas A&M University COM/Scott & White Hospital, 702 SW H.K. Dodgen Loop, MRB, Temple, TX, United States. Tel.: +1 254 742 7055.
    • ,
  • Cynthia J. Meininger

      Affiliations

    • Systems Biology and Translational Medicine, College of Medicine, Texas A&M Health Science Center, Temple, TX, United States

Received 21 December 2009; accepted 25 February 2010. published online 05 April 2010.

Article Outline

Abstract 

Background

Mast cells are recognized as diverse and highly complicated cells. Aside from their notorious role in allergic inflammatory reactions, mast cells are being implicated in numerous disease processes from heart disease to cancer. Mast cells have been implicated in liver pathogenesis including hepatitis and host allograft rejection after liver transplantation.

Aims

The aim of this review is to discuss the traditional function of mast cells, their location and anatomy with regards to hepatic vasculature and the role of mast cells in hepatic diseases including liver regeneration and rejection. Finally, we will touch on the role of mast cells in liver cancer. In conclusion, we hope that the reader comes away with a better understanding of the diverse and potential role(s) that mast cells may play in liver pathologies.

Keywords: Hepatic vasculature, Hepatic fibrosis and histamine, Mediator release

 

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1. Mast cell biology and activation 

The history of the mast cell (MC) goes back over 100 years ago when Paul Ehrlich first described them [1], [2], [3]. Thirty years after the discovery of these “fat, well-fed” cells, he was awarded a Nobel Prize for his discoveries [4]. Many decades later, research on mast cell biology has continued and these cells are becoming increasingly recognised as “cells without limits”, able to illicit positive or negative effects on tissue and organ function.

Mast cells are derived from pluripotent haematopoietic stem cells in the bone marrow that leave and circulate as immature cells only to mature once they reach their destination [5]. This is distinctly different from basophils that mature in the bone marrow before being released into circulation [6]. Once released, mast cells undergo a maturation process that involves numerous factors including the specific cytokine, stem cell factor (SCF) [1], [5], [7]. The SCF receptor, c-Kit, is abundantly expressed in mature mast cells and plays a critical role in the maturation, development and secretory action of mast cells [7], [8].

As Ehrlich described, mast cells are recognisable by their large granules that, after reaction with aniline dyes, exhibit metachromatic staining [1], [2], [6]. These granules contain mediators (like histamine or serotonin) that lie in wait until a signal (e.g., an allergic reaction) is sent to the mast cell for their release. In their traditional role, mast cells are key players in immunoglobulin E (IgE)-associated immune responses via aggregation of the high-affinity IgE receptor, FcɛRI, that is expressed on mast cells as a heterotetrameric receptor with subunits that initiate specific signalling events [1], [9]. Activation by FcɛRI is both highly technical and complicated. Several recent reviews provide a more complete, detailed description of this process [1], [7], [9].

Both positive and negative effects are elicited by FcɛRI including degranulation, gene transcription and eicasanoid production [9]. More recently, it has been noted that mast cells are not regulated solely by IgE-dependent mechanisms. New reports show that mast cells express other surface receptor binding sites such as Toll-like receptors (TLRs) [10], β2-integrins [11], intercellular adhesion molecule-1 (ICAM-1) [11], [12], androgen receptors [13], purinergic P2X receptors (P2X1, P2X4 and P2X7) [14] and the serotonin receptor, 5-HT1A [15]. Further studies have shown that mast cells express vascular endothelial growth factors (VEGF A–D) and the receptors VEGFR1 and VEGFR2 [16], [17], supporting the role of mast cells in angiogenic processes. It has also been demonstrated that certain lipophilic bile acids (like chenodeoxycholic acid) can play a role in activating mast cells and induce an increased release of histamine [18]. Downstream events investigated in activated mast cells include the activation of the small GTPases, Rho and Ras, via activation by SCF [19]. It has also been shown that mast cells express the receptor for corticotropin-releasing hormone [20] and this hormone induces VEGF release through a cAMP/protein kinase A/p38 mitogen activated protein kinase (MAPK)-dependent pathway [21].

Regardless of whether activation is via traditional IgE-mediated mechanisms or another novel receptor-mediated event, mast cells degranulate and secrete mediators into the surrounding tissue. These mediators include biogenic amines like serotonin or histamine, various cytokines and chemokines and leukotrienes [22]. The release of these mediators appears to be dependent upon numerous factors including which protease the mast cell expresses and where the mast cell is located [1], [2], [6].

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2. Mast cell location and heterogeneity 

As stated, mast cells are derived from haematopoietic bone marrow stem cells where they present as undifferentiated CD34+, CD117+ progenitor cells [5], [23]. The road to their destined tissue is complicated. No two mast cells are alike and this diversity is not limited to species, tissue type or organ [23]. All of these factors can influence the final role played by the mast cell.

Mast cells have been identified in multiple organs and tissues of the body, including lung [24], [25], cardiac tissues [26], [27], skin [28], gastrointestinal tract [29], [30], [31], kidney [32], [33] and liver [34], [35]. Within these multiple organ sites, there are two well-known human mast cell classes that are distinguished by enzymatic immunostaining for mast cell proteases, tryptase (MCT) alone or tryptase and chymase together (MCTC) [3], [35]. MCT are found mainly in mucosal sites such as nasal passages whereas MCTC are located within connective tissues like skin [35]. These two populations of mast cells exhibit functional differences. MCT produce cytokines like interleukin 5 (IL-5) and IL-6, whereas MCTC release IL-4 [36]. Studies on human heart mast cells (HHMC), human lung mast cells (HLMC) and human skin mast cells (HSMC) demonstrate that there is also a functional difference following activation of human mast cells. Patella et al. found that stimulation of HSMC by Substance P induced a release of histamine that was not seen in either HHMC or HLMC, whereas protamine stimulation induced histamine release from HHMC and HSMC, but not HLMC [37].

Like human mast cells, mast cells of the rat are a heterogeneous population exhibiting a phenotype resembling either connective tissue- (CTMC) or mucosal-derived mast cells (MMC) [34], [38]. These cells are characterised by staining for two mast cell markers, rat mast cell protease (RMCP) 1 and 2, to distinguish between CTMC (RMCP-1) and MMC (RMCP-2) [34], [38]. Rat MMC have also been shown to predominantly contain histamine, whereas rat CTMC have an abundant amount of both histamine and serotonin [39]. These studies strengthened the notion that mast cells cannot be generalised with regard to species, location or function and this heterogeneous quality is likely the tool that mast cells use to adapt to and alter tissue function in response to disease.

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3. Mast cell deficient animal models 

Studies have reported that mice with naturally occurring mutations occurring at the Dominant Spotting (W) locus or the Steel (Sl) locus have a significant decrease in tissue mast cells [40], [41], [42]. These two strains are designated KitW/KitW-v and MgfSl/MgfSl-d, respectively [43], [44], [45], [46]. This nomenclature stems from the identification of a point mutation causing exon skipping resulting in the failure of c-Kit to be expressed on the cell surface (KitW) [43], [45], whereas KitW-v is a mutation in the tyrosine kinase domain reducing intrinsic kinase activity [43], [46]. MgfSl describes a deletion of the entire SCF coding sequence (Mgf; mast cell growth factor) [43], [45], whereas MgfSl-d is an intragenic insertion/deletion mutation resulting in a complete lack of SCF coding sequences [43], [44]. The site of defect is different in these models; KitW/KitW-v mice harbor mutations in the stem cell/mast cell lineage whereas MgfSl/MgfSl-d are defective in the tissue microenvironment required for mast cell development [43]. Whilst these models may be useful, there are significant limitations as these mice are also prone to a multitude of phenotypic abnormalities that are unrelated to mast cell populations [43]. Perhaps a more important discovery was the mast cell “knock-in” mouse [40], [41]. Transplantation of bone marrow into KitW/KitW-v mice restores mast cell populations allowing demonstrating that loss of function may be related directly to mast cell deficiency [40], [41]. A less popular model engineered to study the importance of mast cells is the mast cell-deficient Ws/Ws (white spotting) rat [46], [47], [48]. This model has a reduced level of c-Kit tyrosine receptor kinase activity due to a 12-base deletion in the tyrosine kinase domain of c-Kit [47], [48]. Ws/Ws are deficient in both CTMC and MMC [47], [48], [49], [50] and have been used in studies including cardiac function [51], renal fibrosis [52] and systemic anaphylaxis [53].

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4. Hepatic mast cells and hepatic vasculature 

Since the identification of hepatic mast cells, numerous studies have attempted to expand our knowledge of the location and function of these cells in the liver. Hepatic mast cells have been identified in many areas throughout the liver, however they tend to favour the portal area, including the portal triad and portal tracts [54]. In normal human liver, mast cells have been shown to accumulate, albeit in small numbers, in both portal tracts and within sinusoids of the hepatic lobules [54], suggesting that the appearance of mast cells is not solely dependent upon liver injury, inflammation or damage [55]. Not surprisingly, mast cells were found next to, or in the walls of, blood vessels adjacent to central veins [55]. Hepatic mast cells have also been shown to be mainly associated with connective tissues adjacent to hepatic arteries in both rat and human liver [54], [56]. Koda et al. recently discovered a population of mast cells that accumulate near and around intrahepatic large bile ducts and intrahepatic peribiliary glands termed peribiliary mast cells [57]. These cells were found, in normal livers, to congregate under the biliary lining and throughout the ductal walls and periductal tissue [57]. A population of sinusoidal mast cells has also been described that may be derived from myeloid bone marrow cells [58]. Liver mast cells release numerous mediators including histamine, heparin, tryptase, transforming growth factor-beta 1 (TGF-β1), tumour necrosis factor alpha (TNF-α), interleukins, cytokines and basic fibroblast growth factor (bFGF) [58], [59].

As this review will focus on hepatic mast cells and their role in liver pathophysiology and given the knowledge that hepatic mast cells are found near blood vessels in the rat liver, we give a brief description of the blood supply to and from the liver as well as microanatomy, including types of liver cells and their role in normal and diseased states. There is a constant flow of blood to the liver via two separate blood supplies: the portal vein and the hepatic artery [60], [61]. Terminal branches of the portal vein and hepatic artery come together and the blood mixes entering liver sinusoids [60], [61], [62]. Surrounding the hepatic sinusoids are the parenchymal cells of the liver, hepatocytes. The major function of hepatocytes is the initiation and secretion of bile [63]. Hepatocytes are also in direct contact with the blood supply making them a very influential cell type with regard to liver pathology, including hepatocellular carcinoma (HCC) [63], [64]. After secretion of bile by the hepatocytes, there is modification of bile before it is pumped out of the liver into the gallbladder. Cholangiocytes, cells lining the biliary tract (or bile duct cells), are responsible for the modification and release of bile from the liver [63] as well as for the transport and metabolism of bile acids [65]. Cholangiocytes are typically the target for a number of cholangiopathies including primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) [66], [67].

The blood supply to the biliary tract and cholangiocytes is provided exclusively by the hepatic artery through a structure termed the peribiliary vascular plexus [68], [69]. The peribiliary vascular plexus drains into the hepatic sinusoids via a route termed the peribiliary portal system [68], [69]. This system has been found to be a source rich in vascular growth factors and other vasoactive substances [69]. Activation of peribiliary mast cells has been shown to induce an increased release of certain vasoactive substances (i.e. nitric oxide, endothelin, and histamine) during chronic liver disease [57]. This increase in local vasoactive mediator concentration may be responsible for influencing the haemodynamics of the peribiliary vascular plexus and intrahepatic biliary tree.

The flow of blood through the liver is not a passive event and blood flow in and out of the liver directly influences the microanatomy of the liver and how it responds to stress and/or disease. It has been shown in rats with bile duct ligation-induced cholestasis that, after interruption of hepatic artery blood supply via hepatic artery ligation, there is a significant loss of the peribiliary vascular plexus and increased cholangiocyte apoptosis coupled with ductopenia [68]. Ischaemic bile duct injury may also occur during liver transplantation coupled with hepatic artery thrombosis [70]. This event can lead to the development of biliary casts, bile duct death or chronic disease that mimics PSC [70].

The parenchyma of the liver is a complicated structure with numerous cell types having different functions in normal liver function and disease response. These include: Kupffer cells [71], [72], hepatic stellate cells [73], [74], [75], sinusoidal endothelial cells [71], [76], vascular endothelial cells [77], fibroblasts [78] and pit cells [71], [79]. As the majority of these cells play a definitive role in liver pathophysiology and presumably interact with hepatic mast cells, we have provided a table (Table 1) outlining these various liver cells and their location as well as their function in the liver. Their interactions with mast cells are discussed in the following sections.

Table 1. Description of liver cell nomenclature, type, location and function.
Nomenclature and cell typeLocationFunction in normal liverRole in liver pathologiesInteraction with mast cellsReferences
Cholangiocytes (epithelial cells)Line the bile ductsModification & secretion of bile; transport of bile acidsCholangiopathies (PBC & PSC) & CCH
MC quantity around inflamed bile ducts		[51], [53], [54], [55]
Hepatocytes (parenchymal cells)Surround the hepatic sinusoidsSynthesis of cholesterol; initiates the formation & secretion of bileAlcoholic cirrhosis, HCCMC quantity
as HCC
[51], [52]
Kupffer cells (NPC, macrophages)Within the hepatic sinusoidRemoval of bacteria and old, unwanted cellsHepatic toxicity and carcinogenesisRecruitment of inflammatory mediators[59], [60]
Hepatic stellate cells (HSC)a (mesenchymal cells/pericytes)The space of Disse (between the hepatocyte & sinusoid)Storage of vitamin A; ECM remodelling; regulator of sinusoidal blood flowLiver fibrosis; cirrhosis; non-cirrhotic portal hypertensionRecruitment of inflammatory mediators[50], [61], [62]
Sinusoidal endothelial cells (SEC)Make up the lining of the hepatic sinusoidFiltration; antigen-presenting cellsLiver fibrosis; alcohol-induced cirrhosisContribute to the capillarisation of sinusoids; recruitment of inflammatory mediators[59], [63]
Pit cells
Liver-specific NK cells		Sinusoidal lumenEliminate tumour cellsCarcinogenesisInteraction unknown[59], [66]
Vascular endothelial cellsLine blood vesselsSupport & protect vascular bedAngiogenesis & liver developmentInteraction unknown[64]
Portal fibroblastsPortal areaMaintenance of homeostatic stateEarly biliary fibrosisInteraction unknown[65]

PBC=primary biliary cirrhosis; PSC=primary sclerosing cholangitis; CCH=cholangiocarcinoma; HCC=hepatocellular carcinoma; NPC=nonparenchymal cells; ECM=extracellular matrix; NK=natural killer; MC=mast cells.

aHSC formerly known as Ito (or fat-storing) cells.

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5. Liver pathologies and hepatic mast cells 

Hepatic mast cells consistently increase in number with progression of various liver diseases. Studies of cirrhosis, fibrosis, hepatitis and other cholangiopathies demonstrate that, histologically, hepatic mast cell counts generally increase as diseases progress [57], [80], [81], [82], implicating a significant role for mast cells in hepatic disorders. During systemic mast cell activation syndrome patients with elevated cholesterol levels also display increased liver transaminases and bilirubin levels suggesting that mast cell activation plays a part in liver abnormalities of unknown etiology [83]. These studies, and others, warrant an evaluation of mast cells during liver disease and progression.

5.1. Primary biliary cirrhosis 

PBC is classified as an autoimmune disease of the liver that is characterised by the progressive loss of small bile ducts (lined by small cholangiocytes) [66], [67]. As these ducts are damaged, bile builds up in the liver over time and damages the tissue. These events can lead to fibrosis and cirrhosis [66], [67]. Mast cell quantity has been shown to increase in PBC by staining for either toluidine blue [54] or immunohistochemical staining for tryptase and chymase [59], [80], evidence that these cells are presumably MCTC. Increased plasma histamine levels were also found in patients with both PBC and PSC, in contrast to healthy patients, raising the possibility of a role for in vivo mast cell activation and mediator release in these diseases [84]. An increase in mast cell number in PBC has also been linked to the secretion of fibrogenic mediators like bFGF, as mast cells positive for bFGF congregated in the fibrotic portal tracts and fibrous septa as well as the fibrotic biliary tree [59]. These cells also had an overexpression of histamine suggesting that the release of histamine and bFGF from mast cells may be responsible for the progression of fibrosis seen in PBC [59]. More recently, in a cholestatic rat model (bile duct ligation-induced), mast cells were found to accumulate in the portal triad and around the proliferating bile ducts [85]. After 14 days of bile duct ligation, mast cell quantity remained similar to sham-operated rats, but increased significantly after 4 days of recanalisation of the ligated common bile duct [85] with high expression found around the remaining proliferating bile ducts. Coupled with the increase in mast cell quantity was the disappearance of bile ducts via apoptosis suggesting that mast cells contribute to the remodelling of the liver during the progression and resolution of PBC [85].

Studies investigating the mechanisms by which mast cells may be involved (either detrimentally or beneficially) and interact in diseases like PBC are limited. One could speculate that the involvement of mast cells in the resolution of PBC may be related to the increased or decreased release of histamine into the microenvironment caused by the interaction of bile acids [18]. To date, the bile acid ursodeoxycholic acid (UDCA) is the most common treatment choice to slow the progression of PBC [86]. UDCA-induced activation of mast cells produces undetectable amounts of histamine [18], suggesting that this bile acid has a protective effect in regards to PBC progression by inhibiting or attenuating the release of inflammatory mediators like histamine.

5.2. Primary sclerosing cholangitis 

Another autoimmune disorder of the liver is PSC. This disease also affects the bile ducts (cholangiocytes) of the liver by increasing inflammation and causing scarring of cholangiocytes [66], [67]. Bile flow is impeded leading to cirrhosis and eventual liver failure. PSC is highly associated with inflammatory bowel disease, particularly ulcerative colitis [87] as well as cholangiocarcinoma, cancer of the biliary tree [88]. Similar to PBC, hepatic mast cell expression and quantity have been shown to increase in patients with PSC compared to healthy controls. Increased mast cell infiltration (detected by anti-human mast cell tryptase) has been noted in bile ducts in patients with early stage PSC with a diffuse staining in the fibrous septa in the late stage of PSC [89]. A further study was performed to detect the expression of SCF in damaged bile ducts as well as mast cell expression in relation to portal fibrosis in liver sections from PSC patients. The authors found that SCF was expressed in the epithelia of destroyed bile ducts in patients with PSC and that c-Kit-positive mast cells accumulated and increased in the portal tract of PSC patients [90].

Because PSC is closely associated with ulcerative colitis (up to 70% of patients have both diseases concurrently) it stands to reason that mast cells and their mediators play a role in these autoimmune, inflammatory diseases. The infiltration of mast cells seen in patients with PSC [89] has been likened to that seen in ulcerative colitis [91] and other inflammatory bowel diseases like Crohn's disease, where there is a significant increase in IL-6-positive mast cells [91], [92]. Mast cell mediators like histamine, mast cell proteases, heparin, cytokines and platelet activating factor have also been shown to play both helpful and harmful roles in various inflammatory bowel diseases [91]. This information may offer new insights for the treatment options for PSC sufferers, as liver transplantation is currently the only definitive “cure” for PSC [87].

5.3. Hepatic fibrosis and hepatitis 

Hepatic fibrosis is a complicated process involving collagen build-up, extracellular matrix turnover and eventual remodelling of the liver. This process encompasses the accumulation of interstitial or “scar” extracellular matrix after liver injury [93]. PBC and PSC can both develop into cirrhosis, the end-stage of progressive fibrosis. A characteristic marker of this end-stage fibrosis are rings of scar that accumulate around the nodules of hepatocytes [93]. Several cell types are implicated in fibrosis progression with the main focus being on the hepatic stellate cell [74]. Years of research have demonstrated that, when activated, hepatic stellate cells take on phenotypes similar to those of myofibroblasts and inflammatory cells and become both proliferative and fibrogenic [94]. In addition to hepatic stellate cells, sinusoidal endothelial cells may also lose their fenestrated structure after injury and begin to express pro-inflammatory molecules like ICAM-1, VEGF and other adhesion molecules [75]. Hepatic stellate cells also begin to express ICAM-1, chemokine receptors and TLRs [94]. These qualities, taken on by both hepatic stellate cells and sinusoidal endothelial cells, are very similar to those of mast cells.

During fibrosis and hepatic disease progression (i.e. hepatitis), hepatocytes maintain a close interaction with other resident cell types as well as inflammatory cells. These populations come together to induce “sinusoidal capillarisation” which describes the events that cause the sinusoids to resemble capillaries [95]. Capillarisation inhibits the normal processes of exchange between hepatocytes and plasma and has been found to be a condition that worsens liver function [95]. As hepatocytes undergo necrosis, inflammatory cells are recruited (including mast cells) and Kupffer cells are activated, causing an increase in local cytokine and growth factor release [96], [97]. Hepatic stellate cells are the primary target of this event and thus are the most important contributing cell type in extracellular matrix deposition. As the basement membrane components increase, causing the formation of continuous basement membrane-like structures in Disse's space, there is also a decrease in the amount of endothelial fenestrae [97], [98], [99], [100]. A role for mast cells in this process has been investigated. Studies suggest that mast cells contribute to capillarisation by recruiting other liver matrix-producing cells, thus increasing the secretion of cytokines and other mediators during the progression of liver fibrosis [56].

As stated above, mast cells express inflammatory and angiogenic receptors and proteins suggesting that their role in hepatic fibrosis may be equally as important as other resident liver cells. To support this, it has been shown that fibrotic human livers and hepatic stellate cells express and produce SCF, an indication of mast cell activation [101]. Hepatic mast cells have been shown to increase in number in fibrotic tissue compared to normal liver tissue [54] and contribute to the progression of fibrosis via the release of profibrogenic mediators like histamine, tryptase, heparin and bFGF [59]. The link between bFGF and hepatic fibrosis progression has been well documented [102], [103] and mast cell-induced release of bFGF may contribute to extracellular matrix remodelling by interaction with hepatic stellate cells [59]. In PBC over half of the mast cell content of the liver was found in sinusoids (the residence hall for hepatic stellate cells) [54], implying an important relationship between these cells. Co-culture studies of hepatic stellate cells and mast cells demonstrate that hepatic stellate cells interact with mast cells via a mechanism that is blocked (∼50%) by neutralizing antibodies to SCF [101]. In a CCl4-induced fibrosis model, the authors found an increased number of mast cells in portal areas that gradually increased as the degree of fibrosis increased (from 4 to 12 weeks) [104]. They further showed that after treatment with an antioxidant, silymarin, there was decreased expression of portal mast cells that was coupled with activation of hepatic stellate cells and TGF-β1 [104]. A recent study in human liver found that there was a high correlation between the number of chymase- (that were also positive for toluidine blue) and angiotensin II-positive cells during the progression of fibrosis [105]. Angiotensin-converting enzyme (ACE) is a well-known angiotensin II-forming enzyme [106] and angiotensin II is thought to induce tissue fibrosis via expression of TGF-β1 [107]. However, chymase, like ACE, activates the conversion of angiotensin I to angiotensin II and also activates the precursor of TGF-β1. Both angiotensin II and TGF-β1 play a role in hepatic fibrosis progression [108], [109]. This study demonstrated that angiotensin II formation was chymase-dependent rather than ACE-dependent, implicating a role for chymase-positive cells (i.e. mast cells) in hepatic fibrosis [105]. Taken together, these studies suggest that mast cells may play a critical role in many stages of fibrosis and disease progression.

5.4. Liver regeneration and host allograft rejection 

It is commonly believed that the liver is the only organ that can regenerate itself after injury; however new evidence has shown that cardiomyocytes may also be able to perform this function in the heart [110]. Regeneration of the liver is accomplished by the combined effort of numerous cell types that proliferate to compensate for tissue loss. Both cholangiocytes and hepatocytes play a critical role in this process and are activated within hours after injury to repair the liver. Other resident liver cells are also implicated in liver regeneration and limited studies now suggest that resident hepatic mast cells and migratory mast cells may affect liver regeneration and, more importantly, rejection [38], [55]. In the study by O’Keeffe et al., increased mast cell hyperplasia was found in human patients with chronic rejection, but not in acute states [55]. Because chronic rejection is a condition associated with severe bile duct damage likened to that seen in PBC and PSC, this association with hepatic mast cells and rejection seems logical. As seen before [59], hepatic mast cells were found around inflamed and damaged bile ducts in patients with chronic rejection and although present in healthy, post-transplantation subjects, mast cell quantity did not increase [55].

Populations of mast cells have also been investigated in liver regeneration after injury. In the rat liver model of partial hepatectomy, where 70% of the liver is removed, it was demonstrated that hepatic mast cell (expressing RMCP-1, an indication of connective tissue mast cell type) quantity decreased per bile ductule at day 3 post-partial hepatectomy, but returned to normal levels after this time point [38]. The authors found that the majority (between 75 and 99%) of recuperated hepatic mast cells (seen after day 3) expressed both RMCP-1 and RMCP-2, suggesting that a migratory population of mast cells appears in the regenerating liver to compensate for the possible loss of resident hepatic mast cells [38]. Thus, it appears from these studies that mast cells are present during liver regeneration. Activation due to an inflammatory response, like host allograft rejection, may cause hepatic mast cells to release unwanted mediators into the environment adding a detrimental effect during regeneration. Although mast cells in other organs have been shown to express angiogenic receptors like VEGFR2 and VEGF3, supporting their role in angiogenesis and remodelling [16], [17], there appears to be no information regarding hepatic mast cells and their ability to behave as an ally during liver regeneration. Instead, these few studies have shown that whilst resident hepatic mast cells (as well as migratory mast cells) are present in the regenerating liver after injury, their role is not a supportive one. Understanding how to “deactivate” these cells may shed light on potential new therapies useful for improving regeneration and preventing rejection.

5.5. Liver carcinogenesis 

The main immune cell types involved in tumour-associated inflammation include macrophages, dendritic cells, lymphocytes, neutrophils, eosinophils and mast cells [111]. The role of mast cells in carcinogenesis has been studied in numerous types of tumours with contrasting findings. In a study of invasive ductal breast cancer, the authors demonstrated that mast cells engulf and phagocytose cancer cells, suggesting a protective role for mast cells [112]. However, another study involving human primary breast cancer showed that mast cells play a supportive role in the angiogenic process increasing tumour growth [113]. The role of mast cells in liver carcinogenesis has been investigated, but remains slightly elusive. In HCC, a cancer of hepatocytes, it has been found that both mast cell and Kupffer cell quantity decreased with disease progression that was also coupled with decreased cyclooxygenase-2 (Cox-2) expression [114], suggesting that a decrease in inflammatory cells may aide in inhibition of growth. The mechanism by which this event might occur was not investigated, but does suggest that mast cells (along with other inflammatory cells) may have an inhibitory role in hepatocellular tumour differentiation and proliferation. In contrast, another study involving HCC showed that mast cells played a role in angiogenesis of the tumour microenvironment and increased as the disease progressed throughout the four stages [114]. In human tissue from both HCC and intrahepatic cholangiocarcinoma (ICC), a biliary tract cancer, there was an increase in mast cell quantity compared to normal livers suggesting a role for mast cells in both of these liver cancers [115].

In ICC, mast cells were found mainly in the tumour stromal area, whereas in HCC, mast cells were mostly sinusoidal [115]. Whilst mast cell density and location have conflicting impacts on liver carcinogenesis, there might be beneficial information to be gained from the investigation of mast cell mediators. A study was performed using two different HCC cell lines, HuH-6 and HA22T/VGH [116], which have unique mutations and derivations. The authors investigated the effects of histamine and other mediators spontaneously released by mast cells on HCC growth. Using mast cell releasate obtained from the medium of cultured peritoneal mast cells, they found that in HuH-6 cells, granule remnants and histamine both decreased the growth of this cell line via down regulation of β-catenin, Cox-2 and survivin expression coupled with increased cellular apoptosis. In contrast, in HA22T/VGH cells the release of histamine and granule remnants increased cell proliferation [116]. Further studies were performed demonstrating that blocking certain histamine receptors (H1 and H2) reversed the histamine-induced action in these cells [116]. The H2 histamine receptor antagonist, cimetidine, was shown to decrease HCC growth via epidermal growth factor (EGF) signalling and decrease migratory events in an HCC cell line [117]. With respect to cholangiocarcinoma (CCH), data from Alpini and Francis has shown that histamine stimulation alone has no effect on CCH growth, but activation or inhibition of certain histamine receptors can impact CCH growth by either increasing or decreasing tumour progression [118]. Chronic in vivo treatment with histamine in nude mice implanted with CCH cells increased tumour growth [118], whereas long-term treatment with an H3 agonist decreased tumour promotion [119]. Whilst the role of mast cells and mast cell mediators has yet to be unraveled fully in these devastating cancers, there is promise that these cells and, more importantly, their contents may prove to be useful therapeutic targets in the future (Table 2).

Table 2. Location and role of mast cells in liver pathologies.
Liver etiologyMast cell locationMast cell role in disease progressionReferences
Primary biliary cirrhosis (PBC)Portal triad, proliferating and inflamed bile ducts, biliary tree
release of inflammatory mediators (histamine) & pro-fibrogenic factors (bFGF)		[60], [87]
Primary sclerosing cholangitis (PSC)Damaged bile ducts, fibrous septa and portal tracts
in the secretion of inflammatory mediators like histamine, heparin and cytokines		[91], [92], [93], [94]
Hepatic fibrosis and hepatitisHepatic sinusoids, around hepatic stellate cells, portal areas and in fibrotic tissueContribute to “capillarisation” of sinusoids and increased release of inflammatory mediators[55], [57], [60], [97], [98], [99], [107]
Liver transplantation and allograft rejectionSurrounding inflamed and damaged bile ductsIncreased release of inflammatory mediators[39], [56], [60]
Liver carcinogenesisAround damaged cholangiocytes and tumour stromal area (CCH); surrounding destroyed hepatocytes and hepatic sinusoids (HCC)Both inhibitory and stimulatory effects induced by mast cell mediators via numerous signalling pathways[114], [115], [116], [117], [118], [119]

bFGF=basic fibroblast growth factor; CCH=cholangiocarcinoma; HCC=hepatocellular carcinoma; IL-6=interleukin 6.

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6. Concluding remarks and future perspectives 

Research involving mast cell biology and function has exponentially exploded during the last decade. Acceptance of mast cell involvement in disease pathologies besides allergic reactions is becoming more prevalent. No longer considered a passive cell, mast cells are shedding new light on the way that we think about disease progression, whether it is cardiac dysfunction or cirrhosis of the liver. From recent works mentioned in this review, it appears that mast cells do not always play a helpful role in liver pathogenesis (Fig. 1). However, whilst behaving in a detrimental fashion in the majority of studies performed, mast cells are not the sole contributor to these diseases. It cannot be ignored that mast cell-deficient rats (Ws/Ws) still develop fibrosis suggesting that mast cells may not be the only cells stimulating fibrosis but may work in association with other resident liver cells to promote disease [120]. The findings from these studies have provided helpful information whilst generating further unanswered questions that add to our confusion regarding these cells and their role in healthy processes. If they are only present to aide in disease advancement, then why are they present at all? What is their role in normal, healthy processes of the liver? Questions like these and others remain to be answered and it is completion of these quests that will hopefully provide the insight necessary to find new treatments for patients suffering from liver disease.

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Conflict of interest statement 

None declared.

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Acknowledgments 

We acknowledge Dr. Gianfranco Alpini for his assistance with this review. Portions of this work were supported by the Scott & White Nicholas C Hightower Endowed Chair of Gastroenterology.

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References 

  1. Beaven MA. Our perception of the mast cell from paul ehrlich to now. Eur J Immunol. 2009;39:11–25
  2. Vyas H, Krishnaswamy G. Paul ehrlich's “Mastzellen”—from aniline dyes to DNA chip arrays: a historical review of developments in mast cell research. Methods Mol Biol. 2006;315:3–11
  3. Rao KN, Brown MA. Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann NY Acad Sci. 2008;1143:83–104
  4. Piro A, Tagarelli A, Tagarelli G, et al. Paul Ehrlich: the Nobel Prize in physiology or medicine 1908. Int Rev Immunol. 2008;27:1–17
  5. Ishizaka T, Mitsui H, Yanagida M, et al. Development of human mast cells from their progenitors. Curr Opin Immunol. 1993;5:937–943
  6. Yong LC. The mast cell: origin, morphology, distribution, and function. Exp Toxicol Pathol. 1997;49:409–424
  7. Galli SJ, Tsai M, Wershil BK. The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others. Am J Pathol. 1993;142:965–974
  8. Shiohara M, Koike K. Regulation of mast cell development. Chem Immunol Allergy. 2005;87:1–21
  9. Kalesnikoff J, Galli SJ. New developments in mast cell biology. Nat Immunol. 2008;9:1215–1223
  10. Bachelet I, Levi-Schaffer F, Mekori YA. Mast cells: not only in allergy. Immunol Allergy Clin N Am. 2006;26:407–425
  11. Weber S, Babina M, Feller G, et al. Human leukaemic (hmc-1) and normal skin mast cells express beta 2-integrins: characterization of beta 2-integrins and icam-1 on hmc-1 cells. Scand J Immunol. 1997;45:471–481
  12. Stahl JL, Cook EB, Graziano FM, et al. Human conjunctival mast cells: expression of fc epsilonri, c-kit, icam-1, and ige. Arch Ophthalmol. 1999;117:493–497
  13. Chen W, Beck I, Schober W, et al. Human mast cells express androgen receptors but treatment with testosterone exerts no influence on ige-independent mast cell degranulation elicited by neuromuscular blocking agents. Exp Dermatol. 2009;
  14. Wareham K, Vial C, Wykes RC, et al. Functional evidence for the expression of p2×1, p2×4 and p2×7 receptors in human lung mast cells. Br J Pharmacol. 2009;157:1215–1224
  15. Meijers JM . Work conflict and mental disorders. Ned Tijdschr Geneeskd. 1991;135:2097–2098
  16. Detoraki A, Staiano RI, Granata F, et al. Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects. J Allergy Clin Immunol. 2009;123:1142–11491149 e1141–1145
  17. Abdel-Majid RM, Marshall JS. Prostaglandin e2 induces degranulation-independent production of vascular endothelial growth factor by human mast cells. J Immunol. 2004;172:1227–1236
  18. Quist RG, Ton-Nu HT, Lillienau J, et al. Activation of mast cells by bile acids. Gastroenterology. 1991;101:446–456
  19. Schrader JW, Schallhorn A, Grill B, et al. Activation of small gtpases of the ras and rho family by growth factors active on mast cells. Mol Immunol. 2002;38:1181–1186
  20. Cao J, Papadopoulou N, Kempuraj D, et al. Human mast cells express corticotropin-releasing hormone (crh) receptors and crh leads to selective secretion of vascular endothelial growth factor. J Immunol. 2005;174:7665–7675
  21. Cao J, Cetrulo CL, Theoharides TC. Corticotropin-releasing hormone induces vascular endothelial growth factor release from human mast cells via the camp/protein kinase a/p38 mitogen-activated protein kinase pathway. Mol Pharmacol. 2006;69:998–1006
  22. Kinet JP. The high-affinity ige receptor (fc epsilon ri): from physiology to pathology. Annu Rev Immunol. 1999;17:931–972
  23. Bradding P. Human lung mast cell heterogeneity. Thorax. 2009;64:278–280
  24. Agafonov VE, Mitereva DE, Makarova OV, et al. Morphofunctional characterization of mast cells of the skin and the mucous membrane of airways in specific hyposensitization carried out on an experimental model. Zh Mikrobiol Epidemiol Immunobiol. 2006;61–65
  25. Weidner N, Austen KF. Ultrastructural and immunohistochemical characterization of normal mast cells at multiple body sites. J Invest Dermatol. 1991;96:26S–30S[discussion 30S–31S, 60S–65S]
  26. Sperr WR, Bankl HC, Mundigler G, et al. The human cardiac mast cell: localization, isolation, phenotype, and functional characterization. Blood. 1994;84:3876–3884
  27. Patella V, Marino I, Lamparter B, et al. Human heart mast cells. Isolation, purification, ultrastructure, and immunologic characterization. J Immunol. 1995;154:2855–2865
  28. Meindl S, Schmidt U, Vaculik C, et al. Characterization, isolation, and differentiation of murine skin cells expressing hematopoietic stem cell markers. J Leukoc Biol. 2006;80:816–826
  29. Wallon C, Soderholm JD. Corticotropin-releasing hormone and mast cells in the regulation of mucosal barrier function in the human colon. Ann NY Acad Sci. 2009;1165:206–210
  30. Bischoff SC. Physiological and pathophysiological functions of intestinal mast cells. Semin Immunopathol. 2009;31:185–205
  31. Traver E, Torres R, de Mora F, et al. Mucosal mast cells mediate motor response induced by chronic oral exposure to ovalbumin in the rat gastrointestinal tract. Neurogastroenterol Motil. 2010;22:e34–e43
  32. Ehara T, Shigematsu H. Mast cells in the kidney. Nephrology (Carlton). 2003;8:130–138
  33. Blank U, Essig M, Scandiuzzi L, et al. Mast cells and inflammatory kidney disease. Immunol Rev. 2007;217:79–95
  34. Chan A, Cooley MA, Collins AM. Mast cells in the rat liver are phenotypically heterogeneous and exhibit features of immaturity. Immunol Cell Biol. 2001;79:35–40
  35. Irani AA, Schechter NM, Craig SS, et al. Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci USA. 1986;83:4464–4468
  36. Bradding P, Okayama Y, Howarth PH, et al. Heterogeneity of human mast cells based on cytokine content. J Immunol. 1995;155:297–307
  37. Patella V, de Crescenzo G, Ciccarelli A, et al. Human heart mast cells: a definitive case of mast cell heterogeneity. Int Arch Allergy Immunol. 1995;106:386–393
  38. Zweifel M, Breu K, Matozan K, et al. Restoration of hepatic mast cells and expression of a different mast cell protease phenotype in regenerating rat liver after 70%-hepatectomy. Immunol Cell Biol. 2005;83:587–595
  39. Welle M. Development, significance, and heterogeneity of mast cells with particular regard to the mast cell-specific proteases chymase and tryptase. J Leukoc Biol. 1997;61:233–245
  40. Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in w/wv mice and their increase by bone marrow transplantation. Blood. 1978;52:447–452
  41. Kitamura Y, Shimada M, Hatanaka K, et al. Development of mast cells from grafted bone marrow cells in irradiated mice. Nature. 1977;268:442–443
  42. Hayashi C, Sonoda T, Nakano T, et al. Mast-cell precursors in the skin of mouse embryos and their deficiency in embryos of sl/sld genotype. Dev Biol. 1985;109:234–241
  43. Wershil BK. Ix. Mast cell-deficient mice and intestinal biology. Am J Physiol Gastrointest Liver Physiol. 2000;278:G343–G348
  44. Brannan CI, Lyman SD, Williams DE, et al. Steel-dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. Proc Natl Acad Sci USA. 1991;88:4671–4674
  45. Galli SJ, Zsebo KM, Geissler EN. The kit ligand, stem cell factor. Adv Immunol. 1994;55:1–96
  46. Nocka K, Tan JC, Chiu E, et al. Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, wv, w41 and w. EMBO J. 1990;9:1805–1813
  47. Tei H, Kasugai T, Tsujimura T, et al. Characterization of cultured mast cells derived from ws/ws mast cell-deficient rats with a small deletion at tyrosine kinase domain of c-kit. Blood. 1994;83:916–925
  48. Tsujimura T, Hirota S, Nomura S, et al. Characterization of ws mutant allele of rats: a 12-base deletion in tyrosine kinase domain of c-kit gene. Blood. 1991;78:1942–1946
  49. Arizono N, Kasugai T, Yamada M, et al. Infection of nippostrongylus brasiliensis induces development of mucosal-type but not connective tissue-type mast cells in genetically mast cell-deficient ws/ws rats. Blood. 1993;81:2572–2578
  50. Niwa Y, Kasugai T, Ohno K, et al. Anemia and mast cell depletion in mutant rats that are homozygous at “White spotting (ws)” locus. Blood. 1991;78:1936–1941
  51. Kennedy RH, Hauer-Jensen M, Joseph J. Cardiac function in hearts isolated from a rat model deficient in mast cells. Am J Physiol Heart Circ Physiol. 2005;288:H632–H637
  52. Miyazawa S, Hotta O, Doi N, et al. Role of mast cells in the development of renal fibrosis: use of mast cell-deficient rats. Kidney Int. 2004;65:2228–2237
  53. Shibamoto T, Shimo T, Cui S, et al. The roles of mast cells and Kupffer cells in rat systemic anaphylaxis. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2202–R2209
  54. Farrell DJ, Hines JE, Walls AF, et al. Intrahepatic mast cells in chronic liver diseases. Hepatology. 1995;22:1175–1181
  55. O’Keeffe C, Baird AW, Nolan N, et al. Mast cell hyperplasia in chronic rejection after liver transplantation. Liver Transpl. 2002;8:50–57
  56. Franceschini B, Ceva-Grimaldi G, Russo C, et al. The complex functions of mast cells in chronic human liver diseases. Dig Dis Sci. 2006;51:2248–2256
  57. Koda W, Harada K, Tsuneyama K, et al. Evidence of the participation of peribiliary mast cells in regulation of the peribiliary vascular plexus along the intrahepatic biliary tree. Lab Invest. 2000;80:1007–1017
  58. Bardadin KA, Scheuer PJ. Mast cells in acute hepatitis. J Pathol. 1986;149:315–325
  59. Yamashiro M, Kouda W, Kono N, et al. Distribution of intrahepatic mast cells in various hepatobiliary disorders. An immunohistochemical study. Virchows Arch. 1998;433:471–479
  60. Michels NA. Newer anatomy of the liver and its variant blood supply and collateral circulation. Am J Surg. 1966;112:337–347
  61. Rappaport AM. Hepatic blood flow: morphologic aspects and physiologic regulation. Int Rev Physiol. 1980;21:1–63
  62. Vidal-Vanaclocha F, Barbera-Guillem E. Fenestration patterns in endothelial cells of rat liver sinusoids. J Ultrastruct Res. 1985;90:115–123
  63. Esteller A. Physiology of bile secretion. World J Gastroenterol. 2008;14:5641–5649
  64. Dooley S, Weng H, Mertens PR. Hypotheses on the role of transforming growth factor-beta in the onset and progression of hepatocellular carcinoma. Dig Dis. 2009;27:93–101
  65. Xia X, Francis H, Glaser S, et al. Bile acid interactions with cholangiocytes. World J Gastroenterol. 2006;12:3553–3563
  66. Alpini G, Prall RT, LaRusso NF. The pathobiology of biliary epithelia. In:  Arias IM,  Boyer JL,  Chisari FV,  Fausto N,  Jakoby W,  Schachter D,  Shafritz DA editor. The Liver, Biology & Pathobiology. 4th ed.. Philadelphia, PA: Lippincott Williams & Wilkins; 2001;p. 421–435
  67. Birnbaum A, Suchy FJ. The intrahepatic cholangiopathies. Semin Liver Dis. 1998;18:263–269
  68. Gaudio E, Barbaro B, Alvaro D, et al. Administration of r-vegf-a prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats. Am J Physiol Gastrointest Liver Physiol. 2006;291:G307–G317
  69. Gaudio E, Franchitto A, Pannarale L, et al. Cholangiocytes and blood supply. World J Gastroenterol. 2006;12:3546–3552
  70. Deltenre P, Valla DC. Ischemic cholangiopathy. Semin Liver Dis. 2008;28:235–246
  71. Kmiec Z. Cooperation of liver cells in health and disease. Adv Anat Embryol Cell Biol. 2001;161:1–151
  72. Roberts RA, Ganey PE, Ju C, et al. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci. 2007;96:2–15
  73. Sato M, Suzuki S, Senoo H. Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct Funct. 2003;28:105–112
  74. Atzori L, Poli G, Perra A. Hepatic stellate cell: a star cell in the liver. Int J Biochem Cell Biol. 2009;41:1639–1642
  75. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88:125–172
  76. Okanoue T, Mori T, Sakamoto S, et al. Role of sinusoidal endothelial cells in liver disease. J Gastroenterol Hepatol. 1995;10(Suppl. 1):S35–S37
  77. Lenzi R, Alpini G, Liu MH, et al. Von willebrand factor antigen is not an accurate marker of rat and guinea pig liver endothelial cells. Liver. 1990;10:372–379
  78. Li Z, Dranoff JA, Chan EP, et al. Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology. 2007;46:1246–1256
  79. Vermijlen D, Luo D, Robaye B, et al. Pit cells (hepatic natural killer cells) of the rat induce apoptosis in colon carcinoma cells by the perforin/granzyme pathway. Hepatology. 1999;29:51–56
  80. Matsunaga Y, Terada T. Mast cell subpopulations in chronic inflammatory hepatobiliary diseases. Liver. 2000;20:152–156
  81. Nakamura A, Yamazaki K, Suzuki K, et al. Increased portal tract infiltration of mast cells and eosinophils in primary biliary cirrhosis. Am J Gastroenterol. 1997;92:2245–2249
  82. Stoyanova II. Relevance of mast cells and hepatic lobule innervation to liver injury. Rom J Gastroenterol. 2004;13:203–209
  83. Alfter K, von Kugelgen I, Haenisch B, et al. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. Liver Int. 2009;29:181–186
  84. Gittlen SD, Schulman ES, Maddrey WC. Raised histamine concentrations in chronic cholestatic liver disease. Gut. 1990;31:96–99
  85. Takeshita A, Shibayama Y. Role of mast cells in hepatic remodeling during cholestasis and its resolution: relevance to regulation of apoptosis. Exp Toxicol Pathol. 2005;56:273–280
  86. Crosignani A, Battezzati PM, Invernizzi P, et al. Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008;14:3313–3327
  87. Chapman R, Cullen S. Etiopathogenesis of primary sclerosing cholangitis. World J Gastroenterol. 2008;14:3350–3359
  88. Abbas G, Lindor KD. Cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Cancer. 2009;40:19–25
  89. Tsuneyama K, Saito K, Ruebner BH, et al. Immunological similarities between primary sclerosing cholangitis and chronic sclerosing sialadenitis: report of the overlapping of these two autoimmune diseases. Dig Dis Sci. 2000;45:366–372
  90. Ishii M, Iwai M, Harada Y, et al. A role of mast cells for hepatic fibrosis in primary sclerosing cholangitis. Hepatol Res. 2005;31:127–131
  91. He SH. Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol. 2004;10:309–318
  92. Middel P, Reich K, Polzien F, et al. Interleukin 16 expression and phenotype of interleukin 16 producing cells in crohn's disease. Gut. 2001;49:795–803
  93. Friedman SL. Mechanisms of disease: mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 2004;1:98–105
  94. Jiao J, Friedman SL, Aloman C. Hepatic fibrosis. Curr Opin Gastroenterol. 2009;25:223–229
  95. Xu GF, Wang XY, Ge GL, et al. Dynamic changes of capillarization and peri-sinusoid fibrosis in alcoholic liver diseases. World J Gastroenterol. 2004;10:238–243
  96. Neubauer K, Saile B, Ramadori G. Liver fibrosis and altered matrix synthesis. Can J Gastroenterol. 2001;15:187–193
  97. Duffield JS, Forbes SJ, Constandinou CM, et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest. 2005;115:56–65
  98. Mori T, Okanoue T, Sawa Y, et al. Defenestration of the sinusoidal endothelial cell in a rat model of cirrhosis. Hepatology. 1993;17:891–897
  99. Neubauer K, Kruger M, Quondamatteo F, et al. 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. 1999;31:692–702
  100. Xu GF, Li PT, Wang XY, et al. Dynamic changes in the expression of matrix metalloproteinases and their inhibitors, timps, during hepatic fibrosis induced by alcohol in rats. World J Gastroenterol. 2004;10:3621–3627
  101. Gaca MD, Pickering JA, Arthur MJ, et al. Human and rat hepatic stellate cells produce stem cell factor: a possible mechanism for mast cell recruitment in liver fibrosis. J Hepatol. 1999;30:850–858
  102. Peng X, Wang B, Wang T, et al. Expression of basic fibroblast growth factor in rat liver fibrosis and hepatic stellate cells. J Huazhong Univ Sci Technol Med Sci. 2005;25:166–169222
  103. Napoli J, Prentice D, Niinami C, et al. Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor beta in a bile duct ligated rat model of cirrhosis. Hepatology. 1997;26:624–633
  104. Jeong DH, Lee GP, Jeong WI, et al. Alterations of mast cells and tgf-beta1 on the silymarin treatment for ccl(4)-induced hepatic fibrosis. World J Gastroenterol. 2005;11:1141–1148
  105. Komeda K, Jin D, Takai S, et al. Significance of chymase-dependent angiotensin ii formation in the progression of human liver fibrosis. Hepatol Res. 2008;38:501–510
  106. Fyhrquist F, Saijonmaa O. Renin–angiotensin system revisited. J Intern Med. 2008;264:224–236
  107. Kagami S, Border WA, Miller DE, et al. Angiotensin ii stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest. 1994;93:2431–2437
  108. Takai S, Jin D, Sakaguchi M, et al. A novel chymase inhibitor, 4-[1-([bis-(4-methyl-phenyl)-methyl]-carbamoyl)3-(2-ethoxy-benzyl)-4-oxo-a zetidine-2-yloxy]-benzoic acid (bceab), suppressed cardiac fibrosis in cardiomyopathic hamsters. J Pharmacol Exp Ther. 2003;305:17–23
  109. Shimizu S, Satomura K, Aramaki T, et al. Hepatic chymase level in chronic hepatitis: co-localization of chymase with fibrosis. Hepatol Res. 2003;27:62–66
  110. Qyang Y, Senyei G. Regeneration of a heart cell. Yale J Biol Med. 2009;82:117–119
  111. Groot Kormelink T, Abudukelimu A, Redegeld FA. Mast cells as target in cancer therapy. Curr Pharm Des. 2009;15:1868–1878
  112. Della Rovere F, Granata A, Monaco M, et al. Phagocytosis of cancer cells by mast cells in breast cancer. Anticancer Res. 2009;29:3157–3161
  113. Ranieri G, Ammendola M, Patruno R, et al. Tryptase-positive mast cells correlate with angiogenesis in early breast cancer patients. Int J Oncol. 2009;35:115–120
  114. Cervello M, Foderaa D, Florena AM, et al. Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: possible role in tumor promotion and angiogenesis. World J Gastroenterol. 2005;11:4638–4643
  115. Terada T, Matsunaga Y. Increased mast cells in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Hepatol. 2000;33:961–966
  116. Lampiasi N, Azzolina A, Montalto G, et al. Histamine and spontaneously released mast cell granules affect the cell growth of human hepatocellular carcinoma cells. Exp Mol Med. 2007;39:284–294
  117. Fujikawa T, Shiraha H, Nakanishi Y, et al. Cimetidine inhibits epidermal growth factor-induced cell signaling. J Gastroenterol Hepatol. 2007;22:436–443
  118. Francis H, DeMorrow H, Venter J, et al. Evidence for a novel role for histamine regulation of cholangiocarcinoma growth by an autocrine mechanism. Gastroenterology. 2008;134:A58
  119. Francis H, Onori P, Gaudio E, et al. H3 histamine receptor-mediated activation of protein kinase c{alpha} inhibits the growth of cholangiocarcinoma in vitro and in vivo. Mol Cancer Res. 2009;[Epub ahead of print] PMID: 19825989
  120. Okazaki T, Hirota S, Xu ZD, et al. 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. 1998;78:1431–1438

PII: S1590-8658(10)00087-3

doi:10.1016/j.dld.2010.02.016

Digestive and Liver Disease
Volume 42, Issue 8 , Pages 529-536, August 2010

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