Comparative Study of the Role of Interepithelial Mucosal Mast Cells in the Context of Intestinal Adenoma-Carcinoma Progression.

Mast cells (MCs) are crucial players in the relationship between the tumor microenvironment (TME) and cancer cells and have been shown to influence angiogenesis and progression of human colorectal cancer (CRC). However, the role of MCs in the TME is controversially discussed as either pro- or anti-tumorigenic. Genetically engineered mouse models (GEMMs) are the most frequently used in vivo models for human CRC research. In the murine intestine there are at least three different MC subtypes: interepithelial mucosal mast cells (ieMMCs), lamina proprial mucosal mast cells (lpMMCs) and connective tissue mast cells (CTMCs). Interepithelial mucosal mast cells (ieMMCs) in (pre-)neoplastic intestinal formalin-fixed paraffin-embedded (FFPE) specimens of mouse models (total lesions n = 274) and human patients (n = 104) were immunohistochemically identified and semiquantitatively scored. Scores were analyzed along the adenoma-carcinoma sequence in humans and 12 GEMMs of small and large intestinal cancer. The presence of ieMMCs was a common finding in intestinal adenomas and carcinomas in mice and humans. The number of ieMMCs decreased in the course of colonic adenoma-carcinoma sequence in both species (p < 0.001). However, this dynamic cellular state was not observed for small intestinal murine tumors. Furthermore, ieMMC scores were higher in GEMMs with altered Wnt signaling (active ß-catenin) than in GEMMs with altered MAPK signaling and wildtypes (WT). In conclusion, we hypothesize that, besides stromal MCs (lpMMCs/CTMCs), particularly the ieMMC subset is important for onset and progression of intestinal neoplasia and may interact with the adjacent neoplastic epithelial cells in dependence on the molecular environment. Moreover, our study indicates the need for adequate GEMMs for the investigation of the intestinal immunologic TME.

Impact of Sequential Lipid Meals on Lymphatic Lipid Absorption and Transport in Rats.

The sequential meal pattern has recently received more attention because it reflects a phycological diet style for human beings. The present study investigated the effects of the second lipid meal on lymphatic lipid absorption and transport in adult rats following a previous lipid meal. Using the well-established lymph fistula model, we found that the second lipid meal significantly increased the lymphatic output of triglycerides, cholesterol, phospholipids, and non-esterified fatty acids compared with a single lipid meal. Besides that, the time reaching the peak of each lipid output was significantly faster compared with the first lipid meal. Additionally, the second lipid meal significantly increased the lymphatic output of apolipoprotein A-IV (ApoA-IV), but not apolipoprotein B-48 (ApoB-48) or apolipoprotein A-I (ApoA-I). Interestingly, the triglyceride/apoB-48 ratio was significantly increased after the second lipid meal, indicating the increased chylomicron size in the lymph. Finally, the second lipid meal increased the lymphatic output of rat mucosal mast cell protease II (RMCPII). No change was found in the expression of genes related to the permeability of lymphatic lacteals, including vascular endothelial growth factor-A (Vegfa), vascular endothelial growth factor receptor 1 (Flt1), and Neuropilin1 (Nrp1). Collectively, the second lipid meal led to the rapid appearance of bigger-sized chylomicrons in the lymph. It also increased the lymphatic output of various lipids and apoA-IV, and mucosal mast cell activity in the intestine.

Mucosal Mast Cells as Key Effector Cells in Food Allergies.

Mucosal mast cells (MMCs) localized in the intestinal mucosa play a key role in the development of IgE-mediated food allergies. Recent advances have revealed that MMCs are a distinctly different population from connective tissue mast cells localized in skin and other connective tissues. MMCs are inducible and transient cells that arise from bone marrow-derived mast cell progenitors, and their numbers increase rapidly during mucosal allergic inflammation. However, the mechanism of the dramatic expansion of MMCs and their cell functions are not well understood. Here, we review recent findings on the mechanisms of MMC differentiation and expansion, and we discuss the potential for the inducers of differentiation and expansion to serve as targets for food allergy therapy. In addition, we also discuss the mechanism by which oral immunotherapy, a promising treatment for food allergy patients, induces unresponsiveness to food allergens and the roles of MMCs in this process. Research focusing on MMCs should provide useful information for understanding the underlying mechanisms of food allergies in order to further advance the treatment of food allergies.

Recent advances in mechanisms of food allergy and anaphylaxis.

Food allergens are innocuous proteins that promote tolerogenic adaptive immune responses in healthy individuals yet in other individuals induce an allergic adaptive immune response characterized by the presence of antigen-specific immunoglobulin E and type-2 immune cells. The cellular and molecular processes that determine a tolerogenic versus non-tolerogenic immune response to dietary antigens are not fully elucidated. Recently, there have been advances in the identification of roles for microbial communities and anatomical sites of dietary antigen exposure and presentation that have provided new insights into the key regulatory steps in the tolerogenic versus non-tolerogenic decision-making processes. Herein, we will review and discuss recent findings in cellular and molecular processes underlying food sensitization and tolerance, immunological processes underlying severity of food-induced anaphylaxis, and insights obtained from immunotherapy trials.

Intestinal Mucosal Mast Cells: Key Modulators of Barrier Function and Homeostasis.

The gastrointestinal tract harbours the largest population of mast cells in the body; this highly specialised leukocyte cell type is able to adapt its phenotype and function to the microenvironment in which it resides. Mast cells react to external and internal stimuli thanks to the variety of receptors they express, and carry out effector and regulatory tasks by means of the mediators of different natures they produce. Mast cells are fundamental elements of the intestinal barrier as they regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuro-immune interactions, which are key to functioning of the gut. Disruption of the intestinal barrier is associated with increased passage of luminal antigens into the mucosa, which further facilitates mucosal mast cell activation, inflammatory responses, and altered mast cell⁻enteric nerve interaction. Despite intensive research showing gut dysfunction to be associated with increased intestinal permeability and mucosal mast cell activation, the specific mechanisms linking mast cell activity with altered intestinal barrier in human disease remain unclear. This review describes the role played by mast cells in control of the intestinal mucosal barrier and their contribution to digestive diseases.

Immune Characterization of Bone Marrow-Derived Models of Mucosal and Connective Tissue Mast Cells.

PURPOSE: It is well appreciated that mast cells (MCs) demonstrate tissue-specific imprinting, with different biochemical and functional properties between connective tissue MCs (CTMCs) and mucosal MCs (MMCs). Although in vitro systems have been developed to model these different subsets, there has been limited investigation into the functional characteristics of the 2 major MC subsets. Here, we report the immunologic characterization of 2 MCs subsets developed in vitro from bone marrow progenitors modeling MMCs and CTMCs. METHODS: We grew bone marrow for 4 weeks in the presence of transforming growth factor (TGF)-ß, interleukin (IL)-9, IL-3, and stem cell factor (SCF) to generate MMCs, and IL-4, IL-3, and SCF to generate CTMCs. RESULTS: CTMCs and MMCs differed in growth rate and protease content, but their immune characteristics were remarkably similar. Both subsets responded to immunoglobulin E (IgE)-mediated activation with signaling, degranulation, and inflammatory cytokine release, although differences between subsets were noted in IL-10. CTMCs and MMCs showed a similar toll-like receptor (TLR) expression profile, dominated by expression of TLR4, TLR6, or both subsets were responsive to lipopolysaccharide (LPS), but not poly(I:C). CTMCs and MMCs express receptors for IL-33 and thymic stromal lymphopoietin (TSLP), and respond to these cytokines alone or with modified activation in response to IgE cross-linking. CONCLUSIONS: The results of this paper show the immunologic characterization of bone marrow-derived MMCs and CTMCs, providing useful protocols for in vitro modeling of MC subsets.

Neuropeptide AF Induces Piecemeal Degranulation in Murine Mucosal Mast Cells: A New Mediator in Neuro-Immune Communication in the Intestinal Lamina Propria?

Neuropeptides AF (NPAF), FF (NPFF) and SF (NPSF) are RFamide neuropeptides known to be widely expressed in the mammalian central nervous system, where they fulfill a wide range of functions with pain modulation being the most prominent one. Recent evidence indicates that RFamides act as mediators in mast cell-sensory nerve communications related to allergic disease. Previous work by our group has shown that the expression levels of some members of the Mas-related gene receptor (Mrgpr) family in both enteric neurons and mucosal mast cells change during intestinal inflammation. The Mrgpr subtypes C11 and A4 can be activated by NPAF, while A1 and C11 are triggered by NPFF. The aim of the present study was to investigate whether RFamides of the NPFF group are expressed in the gastrointestinal tract and to identify possible targets and receptors that might be involved in RFamide-associated mast cell modulation. To this end, the expression and distribution patterns of NPFF/AF receptors and the NPFF precursor protein were determined in bone marrow-derived mucosal mast cells (BMMCs) by immunocytochemistry and (RT-) PCR. BMMCs were found to express MrgprA4 and A1, and functional analysis of the effects of NPAF by means of a ß-hexosaminidase assay, mMCP-1 ELISA, electron microscopy and live cell calcium imaging revealed a piecemeal degranulation induced by NPAF. However, knock-out of MrgprA4 and A1 did not reduce the effect of NPAF, indicating that the BMMC response to NPAF was receptor independent. ProNPFF was expressed in neurons and BMMCs, suggesting that both cell types are potential sources of NPAF in situ. Our results show that the RFamide NPAF can be considered as a novel modulator of BMMC activity in the neuro-immune communication in the gastrointestinal tract, although the exact signaling pathway remains to be elucidated. Anat Rec, 00:000-000, 2018. © 2018 Wiley Periodicals, Inc. Anat Rec, 301:1103-1114, 2018. © 2018 Wiley Periodicals, Inc.

Immune Characterization of Bone Marrow-Derived Models of Mucosal and Connective Tissue Mast Cells

PURPOSE: It is well appreciated that mast cells (MCs) demonstrate tissue-specific imprinting, with different biochemical and functional properties between connective tissue MCs (CTMCs) and mucosal MCs (MMCs). Although in vitro systems have been developed to model these different subsets, there has been limited investigation into the functional characteristics of the 2 major MC subsets. Here, we report the immunologic characterization of 2 MCs subsets developed in vitro from bone marrow progenitors modeling MMCs and CTMCs. METHODS: We grew bone marrow for 4 weeks in the presence of transforming growth factor (TGF)-β, interleukin (IL)-9, IL-3, and stem cell factor (SCF) to generate MMCs, and IL-4, IL-3, and SCF to generate CTMCs. RESULTS: CTMCs and MMCs differed in growth rate and protease content, but their immune characteristics were remarkably similar. Both subsets responded to immunoglobulin E (IgE)-mediated activation with signaling, degranulation, and inflammatory cytokine release, although differences between subsets were noted in IL-10. CTMCs and MMCs showed a similar toll-like receptor (TLR) expression profile, dominated by expression of TLR4, TLR6, or both subsets were responsive to lipopolysaccharide (LPS), but not poly(I:C). CTMCs and MMCs express receptors for IL-33 and thymic stromal lymphopoietin (TSLP), and respond to these cytokines alone or with modified activation in response to IgE cross-linking. CONCLUSIONS: The results of this paper show the immunologic characterization of bone marrow-derived MMCs and CTMCs, providing useful protocols for in vitro modeling of MC subsets.

Immune Cell Responses and Cytokine Profile in Intestines of Mice Infected with Trichinella spiralis.

The intestinal phase is critical for trichinellosis caused by Trichinella spiralis (T. spiralis), as it determines both process and consequences of the disease. Several previous studies have reported that T. spiralis induces the initial predominance of a Th1 response during the intestine stage and a subsequent predominance of a Th2 response during the muscle stage. In the present study, immune cells and cytokine profile were investigated in the intestine of mice infected with T. spiralis. The results showed that the number of eosinophils, goblet cells, mucosal mast cells, and 33D1+ dendritic cells (DCs) increased during the intestinal phase of the infection. Among these, eosinophils, goblet cells, and mucosal mast cells continued to increase until 17 days post infection (dpi), and the number of 33D1+ DCs increased compared to wild type; however, it did not change with the days of infection. The mRNA and protein levels of Th1 cytokines IL-2, IL-12, and IFN-γ and the Th2 cytokines IL-4, IL-5, IL-10, IL-13, and TGF-ß were all increased in the tissues of the small intestine in infected mice; however, in general, Th2 cytokines increased more than Th1 cytokines. In conclusion, our findings suggest that T. spiralis infection can induce an increase of small intestine mucosal immune cells and add further evidence to show that the intestinal mucosal immune system of infected mice was induced toward mixed Th1/Th2 phenotypes with the predominance of Th2 response at the early stage of infection.

Pharmacologic inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia.

BACKGROUND: Mucosal mast cells (MMCs) play a central role in the development of symptoms associated with IgE-mediated food allergy. Recently, Notch2-mediated signaling was shown to be involved in proper MMC distribution in the intestinal tract. OBJECTIVE: This study aimed to clarify the mechanism by which Notch signaling regulates MMC distribution in the intestinal mucosa. Furthermore, pharmacologic inhibition of Notch signaling was evaluated as a treatment for symptoms associated with experimental food allergy. METHODS: Bone marrow-derived mast cells generated from mice were cultured with Notch ligands, and then expression of genes associated with MMCs was measured in the cells. In addition, the effect of an inhibitor of Notch signaling on food antigen-induced allergic reactions was examined in a mouse model of food allergy. RESULTS: Notch signaling induced MMC differentiation through upregulation of expression of genes characteristic of MMCs in the presence of IL-3. Some lamina propria cells isolated from the mouse small intestine expressed Notch ligands and were able to upregulate MMC markers in bone marrow-derived mast cells through Notch signaling. In a mouse model of food allergy, administration of a Notch signaling inhibitor led to suppression of food antigen-induced hyperplasia of intestinal MMCs, resulting in alleviation of allergic diarrhea and systemic anaphylaxis. CONCLUSION: Notch signaling contributes to differentiation and accumulation of MMCs in the intestinal mucosa. Thus inhibition of Notch signaling alleviates symptoms associated with experimental food allergy. These results raise the possibility that Notch signaling in mast cells is a novel target for therapy in patients with food allergy.

Developing food allergy: a potential immunologic pathway linking skin barrier to gut.

Immunoglobulin E (IgE)-mediated food allergy is an adverse reaction to foods and is driven by uncontrolled type-2 immune responses. Current knowledge cannot explain why only some individuals among those with food allergy are prone to develop life-threatening anaphylaxis. It is increasingly evident that the immunologic mechanisms involved in developing IgE-mediated food allergy are far more complex than allergic sensitization. Clinical observations suggest that patients who develop severe allergic reactions to food are often sensitized through the skin in early infancy. Environmental insults trigger epidermal thymic stromal lymphopoietin and interleukin-33 (IL-33) production, which endows dendritic cells with the ability to induce CD4 +TH2 cell-mediated allergic inflammation. Intestinal IL-25 propagates the allergic immune response by enhancing collaborative interactions between resident type-2 innate lymphoid cells and CD4 +TH2 cells expanded by ingested antigens in the gastrointestinal tract. IL-4 signaling provided by CD4 +TH2 cells induces emigrated mast cell progenitors to become multi-functional IL-9-producing mucosal mast cells, which then expand greatly after repeated food ingestions. Inflammatory cytokine IL-33 promotes the function and maturation of IL-9-producing mucosal mast cells, which amplify intestinal mastocytosis, resulting in increased clinical reactivity to ingested food allergens. These findings provide the plausible view that the combinatorial signals from atopic status, dietary allergen ingestions, and inflammatory cues may govern the perpetuation of allergic reactions from the skin to the gut and promote susceptibility to life-threatening anaphylaxis. Future in-depth studies of the molecular and cellular factors composing these stepwise pathways may facilitate the discovery of biomarkers and therapeutic targets for diagnosing, preventing, and treating food allergy.

Persistent alterations in colonic afferent innervation in a rat model of postinfectious gut dysfunction: Role for changes in peripheral neurotrophic factors.

BACKGROUND: Visceral hypersensitivity in the inflamed gut is related partly to the effects of peripheral neurotrophic factors (NTFs) on local afferent neurons. However, alterations in sensory afferents of distant areas remain unexplored. Using the Trichinella spiralis infection model, which causes a jejunitis, we investigated the remodeling of colonic afferents and the potential role of NTFs. METHODS: Rats were infected with T. spiralis. Inflammatory-like changes, mucosal mast cells (MMCs) dynamics, and expression of nerve growth factor and glial cell line-derived NTFs (glial cell-derived neurotrophic factor, artemin, and neurturin) were determined in the colon up to day 30 postinfection. Functional responses of colonic afferents were determined assessing changes in the expression of sensory-related markers in thoracolumbar (TL)/lumbosacral (LS) dorsal root ganglias (DRGs) following intracolonic capsaicin. KEY RESULTS: Trichinella spiralis induced an inflammatory-like response within the colon, partly resolved at day 30 postinfection, except for a persistent MMC infiltrate. While the jejunum of infected animals showed an up-regulation in the expression of NTFs, a transitory down-regulation was observed in the colon. Overall, T. spiralis effects on DRGs gene expression were restricted to a transient down-regulation of TPRV1. Stimulation with intracolonic capsaicin induced a down-regulation of TRPV1 levels in TL and LS DRGs, an effect enhanced in LS DRGs of infected animals, regardless the postinfection time considered. CONCLUSIONS & INFERENCES: During intestinal inflammation, spread morphological and functional alterations, including remodeling of visceral afferents, are observed outside the primary region affected by the insult. Similar mechanisms might be operating in states of widespread alterations of visceral sensitivity.

Activation of mucosal mast cells promotes inflammation-related colon cancer development through recruiting and modulating inflammatory CD11b(+)Gr1(+) cells.

Mast cells (MCs) have been reported to be one of the important immunoregulatory cells in promoting the development of colitis-related colon cancer (CRC). It is not clear which MC subtypes play critical roles in CRC progression from colitis to cancer because mucosal mast cells (MMCs) are distinct from connective tissue mast cells (CTMCs) in maintaining intestinal barrier function under homeostatic and inflammatory conditions. In the current study, we found that MMC numbers and the gene expressions of MMC-specific proteases increased significantly in an induced CRC murine model. The production of mast cell protease-1 (mMCP-1) after MMC activation not only resulted in the accumulation of CD11b(+)Gr1(+) inflammatory cells in the colon tissues but also modulated the activities of CD11b(+)Gr1(+) cells to support tumor cell growth and to inhibit T cell activation. Blocking the MMC activity in mice that had developed colitis-related epithelium dysplasia, CD11b(+)Gr1(+) infiltration was reduced and CRC development was inhibited. Our results suggest that MMC activation recruited and modulated the CD11b(+)Gr1(+) cells to promote CRC and that MMCs can be potential therapeutic targets for the prevention of CRC development.

Vagal afferents mediate antinociception of estrogen in a rat model of visceral pain: the involvement of intestinal mucosal mast cells and 5-hydroxytryptamine 3 signaling.

UNLABELLED: Estrogen reportedly facilitates visceral nociception at the spinal or supraspinal level. The present study was aimed to investigate whether estrogen modulates visceral pain through the vagal pathway. Ovariectomized rats received estradiol, which was administered subcutaneously (to act through both the vagal and spinal pathways) or intraduodenally (to preferentially act through the vagal pathway). Luminally applied estradiol induced a rapid and significant decrease in the visceromotor response to colorectal distension, with increased c-Fos expression in nodose ganglion neurons. Systemically injected estradiol increased visceromotor response and c-Fos expression in both nodose and dorsal root ganglion (T6-12) neurons. The antinociceptive effect of estrogen was abolished by surgical vagotomy or chemical denervation of vagal afferents. Both luminally and systemically administered estradiol elicited selective 5-hydroxytryptamine secretion from the duodenum. Granisetron, a 5-hydroxytryptamine 3 receptor antagonist, reversed the antinociceptive effect of estrogen. Intestinal mucosal mast cell stabilizers prevented estradiol-induced antinociception and 5-hydroxytryptamine secretion. Ultrastructural analysis revealed that estradiol caused piecemeal degranulation of intestinal mucosal mast cells. The actions of estradiol were inhibited by an estrogen receptor ß antagonist and mimicked by an estrogen receptor ß agonist. These results suggest that estrogen can trigger vagus-mediated antinociception, which is masked by its spinally mediated pronociception. PERSPECTIVE: This study is the first to show a vagus-mediated estrogenic antinociception, in which the nongenomic estrogen receptor ß-mediated, intestinal mucosal mast cell-derived 5-hydroxytryptamine/5-hydroxytryptamine 3 receptor pathway is involved. This work may provide new insights into the sex hormone modulation of visceral sensitivity related to irritable bowel syndrome and indicate potential therapeutic targets to manage this disease.

New era for mucosal mast cells: their roles in inflammation, allergic immune responses and adjuvant development

To achieve immune homeostasis in such a harsh environment as the intestinal mucosa, both active and quiescent immunity operate simultaneously. Disruption of gut immune homeostasis leads to the development of intestinal immune diseases such as colitis and food allergies. Among various intestinal innate immune cells, mast cells (MCs) play critical roles in protective immunity against pathogenic microorganisms, especially at mucosal sites. This suggests the potential for a novel MC-targeting type of vaccine adjuvant. Dysregulated activation of MCs also results in inflammatory responses in mucosal compartments. The regulation of this yin and yang function of MCs remains to be elucidated. In this review, we focus on the roles of mucosal MCs in the regulation of intestinal allergic reaction, inflammation and their potential as a new target for the development of mucosal adjuvants.

Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier.

OBJECTIVE: Recently, the authors demonstrated altered gene expression in the jejunal mucosa of diarrhoea-predominant irritable bowel syndrome patients (IBS-D); specifically, the authors showed that genes related to mast cells and the intercellular apical junction complex (AJC) were expressed differently than in healthy subjects. The aim of the authors here was to determine whether these alterations are associated with structural abnormalities in AJC and their relationship with mast cell activation and IBS-D clinical manifestations. DESIGN: A clinical assessment and a jejunal biopsy were obtained in IBS-D patients (n=45) and healthy subjects (n=30). Mucosal mast cell number and activation were determined by quantifying CD117(+) cells/hpf and tryptase expression, respectively. Expression and distribution of AJC specific proteins were evaluated by western blot and confocal microscopy. AJC ultrastructure was assessed by transmission electron microscopy. RESULTS: Compared with healthy subjects, IBS-D patients exhibited: (a) increased mast cell counts and activation; (b) increased protein expression of claudin-2, reduced occludin phosphorylation and enhanced redistribution from the membrane to the cytoplasm; and (c) increased myosin kinase expression, reduced myosin phosphatase and, consequently, enhanced phosphorylation of myosin. These molecular alterations were associated with ultrastructural abnormalities at the AJC, specifically, perijunctional cytoskeleton condensation and enlarged apical intercellular distance. Moreover, AJC structural alterations positively correlated both with mast cell activation and clinical symptoms. CONCLUSION: The jejunal mucosa of IBS-D patients displays disrupted apical junctional complex integrity associated with mast cell activation and clinical manifestations. These results provide evidence for the organic nature of IBS-D, a heretofore model disease of functional gastrointestinal disorders.

Somatostatin suppressed the activity of intestinal mucosal mast cells in rats with multiple organ failure / 中华消化杂志

Objective To investigate the effect of somatostatin(SST) on the activity of intestinal mucosal mast cells(IMMC) and its pathological significance in the development of multiple organ failure(MOF). Methods The rat model of MOF was established by the peritoneal injection of zymosan. Thirty minutes after the injection of zymosan, SST at 2.300 ng?kg -1 ?h -1 or 0.023 ng?kg -1 ?h -1 was injected respectively through tail veins. The concentration of histamine and tumor necrosis factor-? (TNF-?) in plasma and intestinal tissue were measured. The pathological alterations of essential organ including intestine, liver, kidney, lung and heart were studied under light microscope. Their corresponding functions were reflected with alanine aminotransferase (ALT), cretinine (Cr) and oxygen pressure (PO 2). In addition, the ultra structure of the IMMC was observed under a transmission electronic microscope. Results Compared with the controlled rats, the rats injected with SST (2.300 ng?kg -1 ?h -1 ) showed less serious inflammatory response under light microscope. ALT and Cr were decreased 53% and 60% respectively. However, the lung ventilation was improved and PO 2 was increased by 50%. The histamine level in the intestinal tissue from rats treated with SST remarkably increased( ( 8.60? 0.50 ) ng/g protein to ( 14.50? 1.08 ) ng/g protein), whilst the plasma histamine level did not show any significant changes. Exogeneous SST also resulted in lower level of TNF-? in intestine but no changes in plasma. Furthermore, degranulation of IMMC from the rats treated with SST was less obvious. Conclusion SST may prevent from or arrest the development of MOF through suppression of the release of inflammatory mediators, such as histamine and TNF-?.

Effects of gut peptides on the activation of mast cells from rat intestinal mucosa in vitro / 中国免疫学杂志

Objective:To investigate the effects of substance P(SP),somatostain(SST) and vasoactive intestinal peptide(VIP) on the activation of rat intestinal mucosal mast cells(IMMC) in vitro.Methods:IMMC isolated and purified from the whole intestines of normal rats were incubated with gut peptides at various concentrations.The histamine concentration in IMMC and their supernate were determined.Furthermore,the ultrastructure of the incubated IMMC was observed under a transmission electronic microscope.Results:①The spontaneous release rate of histamine was (22.86?3.22)%.②SP significantly increased the histamine release rate from IMMC(P0.05)④At the concentration from 1?10 -1 mol/L to 1?10 -8 mol/L,the higher concentration of VIP was used,the lower histamine release rate was observed(P

Effects of substance P on the activity of intestinal mucosal mast cells in rats with multiple organ failure / 中华消化杂志

Objective Multiple organ failure (MOF) has been regarded as a continuous, uncontrolled inflammatory response. Intestinal mucosal mast cells (IMMC) may be involved in MOF. Substance P (SP), one of gut peptides, is an important regulator in the neuro-endocrine-immune network. However, the effects of SP on IMMC, especially in the case of MOF, remain unclear. This study was aimed to investigate the effects of SP on IMMC in the development of MOF. Methods The rat model of MOF was established by injecting zymosan. After thirty minutes of the injection, SP was given through tail veins at the dose of 20 nmol/kg weight and 0.2 nmol/kg weight. The concentrations of histamine and tumor necrosis facfor-?(TNF-?) in plasma and intestine tissues were measured. The pathological alterations of essential organs including intestine, liver, kidney and lung were examined under light microscope. Their corresponding functions were reflected with ALT, Cr and PO 2. The ultrastructure of the IMMC was also observed under a transmission electronic microscope. Results Compared with the controlled rats, those injected with SP showed much more serious inflammatory response under light microscope. Both ALT and Cr increased by about 50%, but PO 2 decreased by about 40%. Histamine level in the intestinal tissue of the rats treated with SP remarkably decreased, whereas the plasma histamine level did not show any significant changes. The level of TNF-? was higher in the intestinal tissue of the rats treated with SP but no change in plasma, and the degranulation of IMMC under transmission electronic microscope was more obvious.Conclusions SP may trigger MOF through acting on IMMC which may release inflammatory mediators such as histamine and TNF-?.