Mast cell activation syndrome:An up-to-date review of literature

Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.

Pancreatic and pulmonary mast cells activation during experimental acute pancreatitis

AIM:To study the activation of pancreatic and pulmonary mast cells and the effect of mast cell inhibition on the activation of peritoneal and alveolar macrophages during acute pancreatitis.METHODS:Pancreatitis was induced by intraductal infusion of 5% sodium taurodeoxycholate in rats.The mast cell inhibitor cromolyn was administered intraperitoneally(i.p.) 30 min before pancreatitis induction.The pancreatic and pulmonary tissue damage was evaluated histologically and mast cells and their state of activation were evaluated.Peritoneal and alveolar macrophages were obtained and the expression of tumor necrosis factor α was determined.Myeloperoxidase activity was measured to evaluate the effect of mast cell inhibition on the progression of the inflammatory process.Finally,the effect of plasma on cultured mast cells or macrophages was evaluated in vitro.RESULTS:The mast cell stabilizer signif icantly reduced inflammation in the pancreas and lung and the activation of alveolar macrophages but had no effect on peritoneal macrophages.Mast cell degranulation was observed in the pancreas during pancreatitis but no changes were observed in the lung.Plasma from rats with pancreatitis could activate alveolar macrophages but did not induce degranulation of mast cells in vitro.CONCLUSION:Pancreatic mast cells play an important role in triggering the local and systemic inflammatory response in the early stages of acute pancreatitis.In contrast,lung mast cells are not directly involved in the inflammatory response related to pancreatic damage.

Possible biological and translational significance of mast cells density in colorectal cancer

Mast cells(MCs), located ubiquitously near blood vessels, are descended from CD34+ hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, the discovery of their sharing in both innate and adaptive immunity has allowed to redefine their crucial interplay on the regulatory function between inflammatory and tumor cells through the release of mediators granule-associated(mainly tryptase and vascular endothelial growth factor). In particular, in several animal and human malignancies it has been well demonstrated that activated c-Kit receptor(c-KitR) and tryptase(an agonist of the proteinase-activated receptor-2) take pivotal part in tumor angiogenesis after the MCs activation, contributing to tumor cells invasion and metastasis. In this review, we focused on crucial MCs density(MCD) role in colorectal cancer(CRC) development and progression angiogenesis-mediated; then, we will analyze the principal studies that have focused on MCD as possible prognostic factor. Finally, we will consider a possible role of MCD as novel therapeutic target mainly by c-KitR tyrosine kinase inhibitors(imatinib, masitinib) and tryptase inhibitors(gabexate and nafamostat mesylate) with the aim to prevent CRC progression.

Eosinophils and mast cells as therapeutic targets in pediatric functional dyspepsia

There is an increasing appreciation for the importance of inflammation as a pathophysiologic entity that contributes to functional gastrointestinal disorders including functional dyspepsia(FD).Importantly,inflammation may serve as a mediator between psychologic and physiologic functions.This manuscript reviews the literature implicating two inflammatory cell types,mast cells and eosinophils,in the generation of dyspeptic symptoms and explores their potential as targets for the treatment of FD.There are a number of inciting events which may initiate an inflammatory response,and the subsequent recruitment and activation of mast cells and eosinophils.These include internal triggers such as stress and anxiety,as well as external triggers such as microbes and allergens.Previous studies suggest that there may be efficacy in utilizing medications directed at mast cells and eosinophils.Evidence exists to suggest that combining "anti-inflammatory" medications with other treatments targeting stress can improve the rate of symptom resolution in pediatric FD.

Roles and relevance of mast cells in infection and vaccination

In addition to their well-established role in allergy mast cells have been described as contributing to functional regulation of both innate and adaptive immune responses in host defense. Mast cells are of hematopoietic origin but typically complete their differentiation in tissues where they express immune regulatory functions by releasing diverse mediators and cytokines. Mast cells are abundant at mucosal tissues which are portals of entry for common infectious agents in addition to allergens. Here, we review the current understanding of the participation of mast cells in defense against infection. We also discuss possibilities of exploiting mast cell activation to provide adequate adjuvant activity that is needed in high-quality vaccination against infectious diseases.

Effect of fexofenadine, a mast cell blocker, in infertile men with significantly increased testicular mast cells

Aim: To investigate the role of fexofenadine, a mast cell blocker, on semen quality in the treatment of infertile men. Methods: The study included 16 Turkish idiopathic infertile men with azoospermia or oligozoospermia who underwent testicular biopsy to examine mast cells containing tryptase. In all patients, a complete medical history, clinical examination, semen analysis and serum hormone assay were carried out. The biopsy specimens were immunohistochemically stained with antihuman tryptase for mast cells. The number of total mast cells per seminiferous tubule was calculated and recorded as mast cell index. The patients were divided into two groups according to their mast cell index: the higher (≥1, n=9) and the lower (<1, n=7) index groups. Fexofenadine was administered orally at a dose of 180 mg/day for 4 to 9 months. Pre-and post-treatment semen parameters, including total motile sperm counts (TMC) were recorded and compared. Spontaneous pregnancies after the treatment were registered. Results: There was no statistically significant difference in TMC between the pre-treatment and post-treatment values in patients with higher and lower mast cell index (P≥0.05). In both groups, nobody had a significant response to the treatment and there was no spontaneous pregnancy after the treatment. Conclusion: Although testicular dysfunction is closely associated with increased number of testicular mast cells, fexofenadine, a mast cell blocker, appears not having any benefit in the treatment of Turkish infertile men with a significant increase in testicular mast cells. (Asian J Androl 2002 Dec; 4: 291-294)

Study on the Role of Mast Cells in the Development of Liver Fibrosis During Diethylnitrosamine （DEN）－induced Hepatocarcinogen

The mast cells(MC)and their roles in the development of liver fibrosis during experimental hepatocarcinogenesis in rats have been studied immunohistochemically and electron microscopically.Pronounced MC hyperplasia occurred after beginning of the treatment of DEN. The vast majority of mast cells in fibrotic livers was present in thickened fibrous septa.Intracellular or pericytial collagen tape IV and laminin staining were found in mast cells,collagen types I,III and fibronectin were negative.Mast cells mainly distributed in proximity to basement membrane and the electron microscopical observation revealed a close topographic relationship between mast cells and fibroblasts. The fibroblasts phagocytized the granules released by mast cells and thus were activated, showing enhanced formation of collagenous fibrils.The mast cells may be derived from blood circulation or replicated in situ. Those findings indicated that mast cells take part in the process of fibrosis at least by two ways:(1)It directly synthesizes the basement membrane components;(2)It stimulates the fibroblasts or other types of cells which have the potential functions in fibrogenesis by releasing granule mediators or cytokines acting upon the fibrosis process.

Decreased expression of serotonin in the jejunum and increased numbers of mast cells in the terminal ileum in patients with irritable bowel syndrome

AIM: To investigate if there are changes in serotonin (5-HT) levels, enterochromaffin (EC) cells and mast cells in small intestinal mucosa of patients with irritable bowel syndrome (IBS). METHODS: Diarrhea-predominant (IBS-D, n = 20), or constipation-predominant (IBS-C, n = 18) IBS patients and healthy controls (n = 20) underwent colonoscopy and peroral small intestinal endoscopy, and mucosal samples were obtained at the descending part of the duodenum, proximal end of jejunum and terminal ileum. High-performance liquid chromatography- electrochemistry and immunohistochemical methods were used to detect 5-HT content, EC cells and mast cells. RESULTS: (1) There were no differences in the number and distribution of EC cells between IBS patients and the normal group. (2) The mucosal 5-HT contents at the duodenum, jejunum and ileum in IBS-C patients were 182 ± 90, 122 ± 54, 61 ± 35 ng/mg protein, respectively, which were all lower than those in the normal group (256 ± 84, 188 ± 91, and 93 ± 45 ng/ mg protein, respectively), with a significant difference at the jejunum (P < 0.05). There were no differences in the small intestinal mucosal 5-HT contents between IBS-D patients and the normal group. The mucosal 5-HT contents at the duodenum were significantly higher than those at the ileum in the three groups (P < 0.001). (3) The numbers of mast cells in patients with IBS-C and IBS-D at the ileum were 38.7 ± 9.4 and 35.8 ± 5.5/highpower field (hpf), respectively, which were significantly more than that in the normal group (29.8 ± 4.4/hpf) (P < 0.001). There was no significant difference in the numbers of mast cells at the other two parts between IBS patients and the normal group. The numbers of mast cells in IBS-C, IBS-D, and normal groups were all significantly higher at the ileum (38.7 ± 9.4, 35.8 ± 5.5, 29.8 ± 4.4/hpf, respectively) than at the duodenum (19.6 ± 4.7, 18.5 ± 6.3, 19.2 ± 3.3/hpf, respectively, P < 0.001). CONCLUSION: The changes in the 5-HT signaling pathway at the jejunum of IBS-C patients and the increase in mast cells in patients with IBS at the terminal ileum may offer evidence to explain the pathogenesis of IBS.

Mast Cells in Adjacent Normal Colon Mucosa rather than Those in Invasive Margin are Related to Progression of Colon Cancer

Objective: Mast cells (MC) reside in the mucosa of the digestive tract as the first line against bacteria and toxins. Clinical evidence has implied that the infiltration of mast cells in colorectal cancers is related to malignant phenotypes and a poor prognosis. This study compared the role of mast cells in adjacent normal colon mucosa and in the invasive margin during the progression of colon cancer. Methods: Specimens were obtained from 39 patients with colon adenomas and 155 patients with colon cancers treated at the Sun Yat-sen University Cancer Center between January 1999 and July 2004. The density of mast cells was scored by an immunohistochemical assay. The pattern of mast cell distribution and its relationship with clinicopathologic parameters and 5-year survival were analyzed. Results: The majority of mast cells were located in the adjacent normal colon mucosa, followed by the invasive margin and least in the cancer stroma. Mast cell count in adjacent normal colon mucosa (MCCadjacent) was associated with pathologic classification, distant metastases and hepatic metastases, although it was not a prognostic factor. In contrast, mast cell count in the invasive margin (MCCinvasive) was associated with neither the clinicopathlogic parameters nor overall survival. Conclusion: Mast cells in the adjacent normal colon mucosa were related to the progression of colon cancer, suggesting that mast cells might modulate tumor progression via a long-distance mechanism.

Assay of Histamine in Single Mast Cells by Capillary Zone Electrophoresis with Electrochemical Detection

Capillary zone electrophoresis was employed for the analysis of histamine in single rat peritoneal mast cells using an amperometric detector. In this method, individual mast cells and then 0.02 mol/L NaOH as a lysing solution are injected into the front end of the separation capillary. A cell injector was constructed for easy injection of single cells. Histamine in single mast cells has been identified and quantified.

Alterations of mast cells and TGF-β1 on the silymarin treatment for CCl_4-induced hepatic fibrosis

AIM: Silymarin is a potent antioxidant, antiinflammatory and anti-fibrogenic agent in the liver, which is mediated by alteration of hepatic Kupffer cell function, lipid peroxidation, and collagen production. Especially, in hepatic fibrogenesis, mast cells are expressed in chronic inflammatory conditions, and promote fibroblast growth and stimulate production of the extracellular matrix by hepatic stellate cells.METHODS: We examined the inhibitory mechanism of silymarin on CCl4-induced hepatic cirrhosis in rats. At 4, 8,and 12 wk, liver tissues were examined histopathologically for fibrotic changes produced by silymarin treatment.RESULTS: In the silymarin with CCl4-treated group,increase of hepatic stellate cells and TGF-β1 production were lower than in the CCl4-treated group at early stages.Additionally, at the late fibrogenic stage, expressions of TGF-β1 were weaker and especially not expressed in hepatocytes located in peripheral areas. Moreover, the number of mast cell in portal areas gradually increased and was dependent on the fibrogenic stage, but those of CCl4+silymarin-treated group decreased significantly.CONCLUSION: Anti-fibrotic and antiinflammatory effects of silymarin were associated with activation of hepatic stellate cells through the expression of TGF-β1 and stabilization of mast cells. These results suggest that silymarin prevent hepatic fibrosis through suppression of inflammation and hypoxia in the hepatic fibrogenesis.

Identification of key pathways and gene expression in the activation of mast cells via calcium flux using bioinformatics analysis

Mast cells are the main effector cells in IgE-associated allergic disorders,and we have reported that mucosal mast cells(MMCs)play a more important role in the development of food allergy(FA).IgE with antigen or calcium ionophore stimulation can lead to the activation of MMCs via a calcium-dependent pathway.The purpose of the present study was to identify gene signatures with IgE/antigen(dinitrophenyl-bovine serum albumin,DNP-BSA)or calcium ionophore(A23187)on the activation of MMCs.Differentially expressed genes between the two types of samples were identified with microarray analysis.Gene ontology functional and pathway enrichment analyses of differentially expressed genes were performed using the database for annotation,visualization,and integrated discovery software.The results showed that IgE/antigen and A23187 could induce degranulation,increase vacuoles,and elevate the cytosolic calcium concentration in MMCs.Furthermore,GeneChip analysis showed that the same 134 mRNAs were altered with IgE/DNP-BSA and A23187,suggesting that DNP-BSA/IgE and A23187 affect the same signal pathway partly in degranulation.KEGG analysis showed that the data were enriched in NF-κB,TNF,MAPK,transcription factor activity,DNA binding,and nucleic acid binding,suggesting that activation of MMCs is a complex process.The results provide new insights on MMCs activation.

Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots:Stress,intestinal hyperpermeability and inflammation

Mast cells (MC) are pivotal elements in several physiological and immunological functions of the gastro- intestinal (GI) tract. MC translate the stress signals that has been transmitted through brain gut axis into release of proinflammatory mediators that can cause stimulation of nerve endings that could affect afferent nerve terminals and change their perception, affect intestinal motility, increase intestinal hyperpermeability and, in susceptible individuals, modulate the inflammation. Thus, it is not surprising that MC are an important element in the pathogenesis of inflammatory bowel disease and non inflammatory GI disorders such as IBS and mast cell enterocolitis.

Probiotic Lactobacillus rhamnosus downregulates FCER1 and HRH4 expression in human mast cells

AIM:To investigate the effects of four probiotic bacteria and their combination on human mast cell gene expression using microarray analysis.METHODS:Human peripheral-blood-derived mast cells were stimulated with Lactobacillus rhamnosus (L.rhamnosus) GG (LGG),L.rhamnosus Lc705 (Lc705),Propionibacterium freudenreichii ssp.shermanii JS (PJS) and Bifidobacterium animalis ssp.lactis Bb12 (Bb12) and their combination for 3 or 24 h,and were subjected to global microarray analysis using an Affymetrix GeneChip Human Genome U133 Plus 2.0 Array.The gene expression differences between unstimulated and bacteria-stimulated samples were further analyzed with GOrilla Gene Enrichment Analysis and Visualization Tool and MeV Multiexperiment Viewer-tool.RESULTS:LGG and Lc705 were observed to suppress genes that encoded allergy-related high-affinity IgE receptor subunits α and γ (FCER1A and FCER1G,respectively) and histamine H4 receptor.LGG,Lc705 and the combination of four probiotics had the strongest effect on the expression of genes involved in mast cell immune system regulation,and on several genes that encoded proteins with a pro-inflammatory impact,such as interleukin (IL)-8 and tumour necrosis factor alpha.Also genes that encoded proteins with anti-inflammatory functions,such as IL-10,were upregulated.CONCLUSION:Certain probiotic bacteria might diminish mast cell allergy-related activation by downregulation of the expression of high-affinity IgE and histamine receptor genes,and by inducing a pro-inflammatory response.

Should mast cells be considered therapeutic targets in multiple sclerosis?

Mast cells are immune cells of the myeloid lineage that are found throughout the body,including the central nervous system.They perform many functions associated with innate and specific immunity,angiogenesis,and vascular homeostasis.Moreover,they have been implicated in a series of pathologies(e.g.,hypersensitivity reactions,tumors,and inflammatory disorders).In this review,we propose that this cell could be a relevant therapeutic target in multiple sclerosis,which is a central nervous system degenerative disease.To support this proposition,we describe the general biological properties of mast cells,their contribution to innate and specific immunity,and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development.The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis,including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.

Hirschsprung's disease:Is there a relationship between mast cells and nerve fibers?

AIM:To define the topography of mast cells and their numbers in cases of Hirschsprung's disease(HD)and non-HD,assess neural hypertrophy using imaging software and to study the relationship between mast cells and nerve fibers.METHODS:HE stained sections of 32 cases of chronic constipation in the age group of 0-14 years were reviewed for ganglion cells.AChE staining was performed on frozen sections of colonic and rectal biopsies.Based on their findings cases were divided into HD and non-HD and mast cells stained by toluidine blue were evaluated.Image analysis by computerized software was applied to S-100 stained sections for assessment of neural hypertrophy.RESULTS:Difference between number of mast cells in HD group(mean=36.44)and in non-HD group(mean =14.79)was statistically significant.Image analysis morphometry on S-100 stained sections served as a useful adjunct.The difference between number,size,and perimeter of the nerve fibers between HD and non-HD group was statistically significant.CONCLUSION:Mast cells are significantly increased in HD and their base line values are much higher in Indian children than that reported in Western literature.Their role in HD needs further research.Morphometry of S-100 stained nerve fibers is a useful adjunct to conventional methods for diagnosis of HD.

Effect of 1,25-dihydroxyvitamin D3 on mast cells tryptase in asthmatic guinea pigs

Objective:To explore the effect of 1,25-dihydroxyvitamin D3 on the mast cell tryptase(MCT) in asthmatic guinea pigs.Methods:A total of 60 male or female healthy guinea pigs were randomly divided into control group(group A),asthmatic group(group B).and 1,25-dihydroxyvitamin D3 group(group C),with 20 cases in each group.To establish asthmatic guinea pig models,1ml peanut oil was tilled into stomach in the morning in group A and group B.and 1 ml peanut oil with 1,25-dihydroxyvitamin D3 was filled into stomach in group C.Airway resistance(Re) of asthmatic guinea pigs was detected,and the bronchoalveolar lavage fluid(BALF) cells were counted.Lung tissue with HE and MCT immunohistochemical staining were used to observe the pathological changes in lung tissue and the distribution of MCT.Results:After injection of different concentration of acetylcholine chloride,the Re in group B and group C were increased significantly compared with group A(P<0.05):compared with group B.the Re in group C were decreased significantly(t=-5.385.-5.761.-6.184.-13.574.P<0.05):the total number of BALF cells and eosinophils were increased significantly in group B and C(t=19.618.9.598.10.854.5.388.P<0.05);compared with group B.the total number of BALF cells and eosinophils in group C was decreased significantly(t=-5.555.-5.392.P<0.05):the number of tryptase positive cells in group B was increased significantly than that in group A(t=21.312,P<0.05),and in addition to the alveolar septum and submucosa,the cells were also distributed around blood vessels and outside the cells:the number of tryptase positive cells in group C was decreased significantly compared with group B.and the difference was statistically significant(t=5.043.P<0.05).Conclusions:After the asthmatic guinea pigs arc treated with 1,25-dihydroxyvitamin D3,their BALF.Re.infiltration degree of inflammatory cells in the trachea and lung tissue and airway inflammatory reaction are reduced significantly.1,25-dihydroxyvitamin D3 has a certain inhibiting effect on the activation of mast cells and the release of MCT granules.

Chronic Stress Induced Proliferation and Activation of Mast Cells of Gastric Antrum in Rats

To explore chronic eration and activation of mast heterotypic stressors induced prolifcells in gastric antrum mucosa by ultrastructure alterations of mast cells, chronic unpredictable heterotypic stressors were used as a study model. The mean immunofluorescence magnitude of mast cell protease 1 （MCP-1） taken from chronic stress rats were 37.4±7.7, significantly higher （p〈0.05） than the value of normal control group （24.8±5.6）. Chronic unpredictable haterotypic stressors appeared also to induce ultrastructure alterations of mast cells. It indicated that mast cells were proliferated and activated, while mast cell granules were hyperplasiaed. Most granules had obvious intragranular changes with loss of electron-dense material. The morphologic evidence showed that macrophages and leukocytes infiltrated in chronic stress rats. Some granules of leukocytes adhered to the surface of mast cell, and formed a bridge. Macrophages phagocytized the mast cell granules.

Mast cells and multiple sclerosis in females and males

Mast cells were observed in autopsies from 11 females and 8 males. We confirm earlier observations that mast cells are more frequent in close vicinity to MS-plaques. In these plaque-border zone areas, defined as the area within 1 mm distance of the actual plaques, the average number of mast cells was 2.34/mm2 in males and 4.77/mm2 in females, which in average is appr. 10 times more than earlier observed in MS. The difference in number of mast cells between females and males is significant (p < 0.005) and is of interest since females are more inclined to developing MS than males. Mast cells were rare in areas without visible plaques. The mast cells were preferably located close to capillaries and venules. A mechanism for the probable role of mast cells, based on diet-factors and mast cell mediators in the pathogenesis of MS is discussed.