scholarly journals Mast Cell Mediated Regulation of Small Intestinal Chloride Malabsorption in SAMP1/YitFc Mouse Model of Spontaneous Chronic Ileitis

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 697
Author(s):  
M Motiur Rahman ◽  
Sheuli Afroz ◽  
Subha Arthur ◽  
Uma Sundaram
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Brush Border Membrane ◽  
Kinetic Studies ◽  
Marker Enzyme ◽  
Mice Model ◽  
Experimental Conditions ◽  
Inflammatory Bowel ◽  
Small Intestinal ◽  
Akr Mice

In Inflammatory Bowel Disease (IBD), malabsorption of electrolytes (NaCl) results in diarrhea. Inhibition of coupled NaCl absorption, mediated by the dual operation of Na:H and Cl:HCO3 exchangers on the brush border membrane (BBM) of the intestinal villus cells has been reported in IBD. In the SAMP1/YitFcs (SAMP1) mice model of spontaneous ileitis, representing Crohn’s disease, DRA (Downregulated in Adenoma) mediated Cl:HCO3 exchange was shown to be inhibited secondary to diminished affinity of the exchanger for Cl. However, NHE3 mediated Na:H exchange remained unaffected. Mast cells and their secreted mediators are known to be increased in the IBD mucosa and can affect intestinal electrolyte absorption. However, how mast cell mediators may regulate Cl:HCO3 exchange in SAMP1 mice is unknown. Therefore, the aim of this study was to determine the effect of mast cell mediators on the downregulation of DRA in SAMP1 mice. Mast cell numbers and their degranulation marker enzyme (β-hexosaminidase) levels were significantly increased in SAMP1 mice compared to control AKR mice. However, treatment of SAMP1 mice with a mast cell stabilizer, ketotifen, restored the β-hexosaminidase enzyme levels to normal in the intestine, demonstrating stabilization of mast cells by ketotifen. Moreover, downregulation of Cl:HCO3 exchange activity was restored in ketotifen treated SAMP1 mice. Kinetic studies showed that ketotifen restored the altered affinity of Cl:HCO3 exchange in SAMP1 mice villus cells thus reinstating its activity to normal. Further, RT-qPCR, Western blot and immunofluorescence studies showed that the expression levels of DRA mRNA and BBM protein, respectively remained unaltered in all experimental conditions, supporting the kinetic data. Thus, inhibition of Cl:HCO3 exchange resulting in chloride malabsorption leading to diarrhea in IBD is likely mediated by mast cell mediators.

scholarly journals Mast Cells as Targets for the Therapy of Inflammatory Bowel Disease

1990 ◽  
Vol 4 (7) ◽  
pp. 285-288
Author(s):  
EY Bissonnette ◽  
RC Benyon ◽  
AD Befus
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mast Cell ◽  
Mast Cells ◽  
Bowel Disease ◽  
Inflammatory Responses ◽  
Therapeutic Interventions ◽  
Cell Hyperplasia ◽  
Beneficial Effects ◽  
Inflammatory Bowel ◽  
Multiple Drugs

The etiology and pathogenesis of inflammatory bowel disease (IBD) is poorly understood. However, numerous studies have demonstrated that immunological and inflammatory responses are activated during this disease. A better understanding of these events will help identify appropriate therapeutic interventions. Mast cell hyperplasia is a prominent feature of inflamed intestinal tissue in IBD. Intestinal mast cells are heterogeneous and at least two populations are present in the human intestine. The authors' objective is to explore mast cell properties, activation and mediators that are involved in the induction, maintenance and perpetuation of inflammatory lesions in the intestine. Although some therapies used in IBD can modulate mast cell activities, whether these actions are important in the beneficial effects of the drugs is unknown. Future drug development targeted to the inhibition of mast cells might be of therapeutic value. However, a cascade of different cellular events are involved in IBD development. The complexity of the disease raises difficulties in the development of therapies. Multiple drugs, selective for different phases of the disease or acting on different cells, might be most appropriate, rather than a single, all-encompassing therapeutic agent.

scholarly journals Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine

Blood ◽  
2011 ◽  
Vol 117 (1) ◽  
pp. 128-134 ◽  
Author(s):  
Mamiko Sakata-Yanagimoto ◽  
Toru Sakai ◽  
Yasuyuki Miyake ◽  
Toshiki I. Saito ◽  
Haruhiko Maruyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Small Intestine ◽  
Mast Cells ◽  
Lamina Propria ◽  
Conditional Knockout ◽  
Small Intestinal Mucosa ◽  
Epithelial Layer ◽  
Strongyloides Venezuelensis ◽  
Small Intestinal

Abstract Notch receptor-mediated signaling is involved in the developmental process and functional modulation of lymphocytes, as well as in mast cell differentiation. Here, we investigated whether Notch signaling is required for antipathogen host defense regulated by mast cells. Mast cells were rarely found in the small intestine of wild-type C57BL/6 mice but accumulated abnormally in the lamina propria of the small-intestinal mucosa of the Notch2-conditional knockout mice in naive status. When transplanted into mast cell–deficient Wsh/Wsh mice, Notch2-null bone marrow-derived mast cells were rarely found within the epithelial layer but abnormally localized to the lamina propria, whereas control bone marrow-derived mast cells were mainly found within the epithelial layer. After the infection of Notch2 knockout and control mice with L3 larvae of Strongyloides venezuelensis, the abundant number of mast cells was rapidly mobilized to the epithelial layer in the control mice. In contrast, mast cells were massively accumulated in the lamina propria of the small intestinal mucosa in Notch2-conditional knockout mice, accompanied by impaired eradication of Strongyloides venezuelensis. These findings indicate that cell-autonomous Notch2 signaling in mast cells is required for proper localization of intestinal mast cells and further imply a critical role of Notch signaling in the host-pathogen interface in the small intestine.

scholarly journals A novel mice model of acute flares in osteoarthritis elicited by intra-articular injection of cultured mast cells

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Junpei Dan ◽  
Masashi Izumi ◽  
Hiroko Habuchi ◽  
Osami Habuchi ◽  
Shogo Takaya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mast Cell ◽  
Mast Cells ◽  
Mice Model ◽  
Inhibitory Effects ◽  
Histological Changes ◽  
New Strategy ◽  
Monosodium Iodoacetate ◽  
Disease Modifying Treatment

Abstract Purpose Mast cells are multifunctional in osteoarthritis (OA), and infiltration of activated mast cells likely contributes to disease severity and progression. However, the detailed mechanisms of action are unclear. The purpose of this study was to elucidate the role of mast cell infiltration in OA at histological level using a new mice model and to investigate pharmacological inhibitory effects of existing mast cell stabilizers in this model. Methods Mice were injected intra-articularly with monosodium iodoacetate (MIA 0.5 mg) or PBS on day 0, and PBS, with or without mast cells (MC: 1 × 106 cells) on day 14. They were divided into four groups: OA flare (MIA + MC), OA (MIA + PBS), MC non-OA (PBS + MC), and PBS non-OA (PBS + PBS). In OA flare, the MC stabilizer drug (tranilast: 400 mg/kg/day) or PBS was administered intraperitoneally from days 15 to 21. Results Histologically, modified Mankin score of the OA flare was significantly higher than that of OA (7.0 [1.8] vs. 3.3 [1.3], P < 0.05), and a larger number of mast cells was observed in OA flare than in OA (34.5 [6.3]/mm2 vs. 27.2 [2.3]/mm2, P < 0.05) on day 22. OA flare also showed acute exacerbation of pain and increased gene expression of pro-inflammatory cytokines and aggrecanase compared with OA. Administration of tranilast to OA flare-up provoked significant improvements in term of histological changes, pain, and gene expression at day 22. Conclusion Our novel model possibly mimics OA flare conditions, which may open a new strategy of disease-modifying treatment for OA, focused on controlling the multiple functions of mast cells.

scholarly journals Mucosal Mast Cells in Irritable Bowel Syndrome and Inflammatory Bowel Disease

2005 ◽  
Vol 48 (3-4) ◽  
pp. 163-164 ◽  
Author(s):  
Bilge Tunc ◽  
Levent Filik ◽  
Engin Altıntas ◽  
Nesrin Turhan ◽  
Aysel Ulker ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mast Cell ◽  
Irritable Bowel Syndrome ◽  
Mast Cells ◽  
Bowel Disease ◽  
Mucosal Mast Cell ◽  
Cell Counts ◽  
Mucosal Mast Cells ◽  
Inflammatory Bowel ◽  
Irritable Bowel

Even though exciting progresses have been until now, further studies are necessary to clearly understand the significance of MMC. Mast cells are thought to participate in the pathogenesis of inflammatory bowel disease and irritable bowel syndrome. However, their role in the pathogenesis remains unsettled. The specific aims of this study were to (1) examine mucosal mast cell counts in the cecum in patient with IBS, and IBD (2) compare MMC between the disease groups. We showed increased MMC count in IBS.

P159 PHENOTYPIC CHARACTERIZATION OF INFLAMMATORY BOWEL DISEASE BIOPSIES REVEAL THAT MAST CELLS ARE SIGNIFICANTLY ELEVATED AND ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S33-S34
Author(s):  
Bradford Youngblood ◽  
Tina Davis ◽  
Julia Schanin ◽  
Melina Butuci ◽  
Emily Brock ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Bowel Disease ◽  
Mast Cell ◽  
Mast Cells ◽  
Inhibitory Activity ◽  
Human Colon ◽  
Colonic Tissue ◽  
Colon Tissue ◽  
Inflammatory Bowel

Abstract Rationale Accumulation and activation of mast cells and eosinophils have been implicated in the pathogenesis of several chronic inflammatory gastrointestinal (GI) diseases, including eosinophilic gastrointestinal diseases (EGIDs) and inflammatory bowel disease (IBD). Despite the strong association of mast cell and eosinophil numbers and activation with the pathogenesis of IBD, no further characterization of these cells has been performed. Current treatment options for IBD include aminosalicylates, antibiotics, immunomodulators, biologic agents and small molecules. These therapies are only moderately effective. A significant proportion of patients fail to respond, do not fully respond, or lose response over time. Therefore, there is significant need for more selective and effective therapy options. Siglec-8 is an inhibitory receptor selectively expressed on human eosinophils and mast cells and represents a novel target for the treatment of IBD with the anti-Siglec-8 mAb, antolimab (AK002). We aimed to quantify and evaluate the activation state of mast cells and eosinophils in colonic tissue from IBD or non-diseased patients. In addition, we quantified the production of TNFa from human colon tissue mast cells and evaluated the inhibitory activity of antolimab (AK002) on these cells. Methods Single-cell suspensions were prepared by enzymatic digestion of fresh colonic biopsies from patients clinically diagnosed with IBD (n=29) or non-diseased control tissues (n=16). Multi-color flow cytometry was performed to identify major immune cell populations and evaluate the activation state of mast cells and eosinophils. Mast cells were FACS-sorted from human colon tissue to evaluate cytokine production and inhibitory activity of antolimab. Results The percentage of mast cells and the expression of the mast cell degranulation marker CD107a were significantly increased in ulcerative colitis (UC) patient biopsy tissue compared to Crohn’s disease (CD) and non-diseased colonic tissue (Figure 1A and B). Furthermore, FACS-sorted mast cells from human colon tissue produced significant quantities of TNFa that was reduced after ex vivo antolimab treatment. Colonic tissue eosinophils were also elevated in a subset of UC and CD patient biopsies, and all UC and CD tissue eosinophils displayed increased expression of the activation marker CD11b compared to control colonic tissue. Conclusions Mast cells and eosinophils may play a significant role in driving the pathogenesis of ulcerative colitis through the production of inflammatory mediators. The high expression of Siglec-8 and the inhibitory activity against mast cells suggests that antibodies that target this receptor, such as antolimab (AK002) represent a potential novel approach for the treatment of IBD.

scholarly journals Mast cell mediated ion transport in intestine from patients with and without inflammatory bowel disease

Gut ◽  
1997 ◽  
Vol 41 (6) ◽  
pp. 785-792 ◽  
Author(s):  
S E Crowe ◽  
G K Luthra ◽  
M H Perdue
Keyword(s):  
Inflammatory Bowel Disease ◽  
Mast Cell ◽  
Small Intestine ◽  
Mast Cells ◽  
Ion Transport ◽  
Bowel Disease ◽  
Short Circuit ◽  
Physiological Role ◽  
Cell Numbers ◽  
Inflammatory Bowel

Background—Mast cells have been shown to regulate intestinal ion transport in animal models and normal human colon but their physiological role in human intestinal inflammatory disorders is unknown.Aims—To examine mast cell regulation of ion transport in inflammatory bowel disease (IBD).Subjects and methods—Small and large intestine was obtained from patients with and without IBD undergoing surgical resection. Short circuit current (Isc) responses to rabbit antihuman IgE, histamine, and electrical stimulation were measured in Ussing chambers. Specimens were also examined for mast cell numbers and degree of inflammation.Results—Isc responses to anti-IgE and histamine were smaller in magnitude in IBD compared with non-IBD tissues. In all tissues, anti-IgE Isc responses were reduced by about 80% in chloride free buffer. The histamine H1 receptor antagonist, pyrilamine, decreased anti-IgE responses in non-IBD tissues. Greater inhibition with pyrilamine was seen in IBD small intestine but its effect was less in IBD colon. Histamine pretreatment of non-IBD control tissues reduced anti-IgE responses to levels seen in IBD colon but had no effect in small intestine. Mast cell numbers were greater in IBD compared with non-IBD small intestine while no differences were observed between the colonic groups. Isc responses to anti-IgE were not correlated with the degree of mucosal inflammation.Conclusions—This study provides further evidence that mast cells are capable of mediating alterations of ion transport in human gut but that this regulatory role may be altered in IBD. The data suggest that prior activation of mast cells with release of histamine may account for the reduced secretory response to anti-IgE observed in IBD colonic tissues.

Neuroimmune interactions in guinea pig stomach and small intestine

2003 ◽  
Vol 284 (1) ◽  
pp. G154-G164 ◽  
Author(s):  
Sumei Liu ◽  
Hong-Zhen Hu ◽  
Na Gao ◽  
Chuanyun Gao ◽  
Guodu Wang ◽  
...  
Keyword(s):  
Mast Cell ◽  
Small Intestine ◽  
Membrane Potential ◽  
Mast Cells ◽  
Receptor Antagonist ◽  
Caffeic Acid ◽  
Neuronal Excitability ◽  
Neuroimmune Interactions ◽  
Small Intestinal ◽  
Β Lactoglobulin

Enteric neuroimmune interactions in gastrointestinal hypersensitivity responses involve antigen detection by mast cells, mast cell degranulation, release of chemical mediators, and modulatory actions of the mediators on the enteric nervous system (ENS). Electrophysiological methods were used to investigate electrical and synaptic behavior of neurons in the stomach and small intestine during exposure to β-lactoglobulin in guinea pigs sensitized to cow's milk. Application of β-lactoglobulin to sensitized preparations depolarized the membrane potential and increased neuronal excitability in small intestinal neurons but not in gastric neurons. Effects on membrane potential and excitability in the small intestine were suppressed by the mast cell stabilizing drug ketotifen, the histamine H2 receptor antagonist cimetidine, the cyclooxygenase inhibitor piroxicam, and the 5-lipoxygenase inhibitor caffeic acid. Unlike small intestinal ganglion cells, gastric myenteric neurons did not respond to histamine applied exogenously. Antigenic exposure suppressed noradrenergic inhibitory neurotransmission in the small intestinal submucosal plexus. The histamine H3receptor antagonist thioperamide and piroxicam, but not caffeic acid, prevented the allergic suppression of noradrenergic inhibitory neurotransmission. Antigenic stimulation of neuronal excitability and suppression of synaptic transmission occurred only in milk-sensitized animals. Results suggest that signaling between mast cells and the ENS underlies intestinal, but not gastric, anaphylactic responses associated with food allergies. Histamine, prostaglandins, and leukotrienes are paracrine signals in the communication pathway from mast cells to the small intestinal ENS.

scholarly journals Inducible Nitric Oxide Regulates Na-Glucose Co-Transport in a Spontaneous SAMP1/YitFc Mouse Model of Chronic Ileitis

Nutrients ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 3116
Author(s):  
Balasubramanian Palaniappan ◽  
Shanmuga Sundaram ◽  
Subha Arthur ◽  
Sheuli Afroz ◽  
Uma Sundaram
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Bowel Disease ◽  
Small Intestine ◽  
Mouse Model ◽  
Brush Border Membrane ◽  
Common Symptom ◽  
Samp1 Mouse ◽  
Inflammatory Bowel ◽  
Akr Mice ◽  
Inducible Nitric Oxide

In mammalian small intestine, glucose is primarily absorbed via Na-dependent glucose co-transporter (SGLT1) on the brush border membrane (BBM) of absorptive villus cells. Malabsorption of nutrients (e.g., glucose) leads to malnutrition, a common symptom of inflammatory bowel disease (IBD), where the mucosa is characterized by chronic inflammation. Inducible nitric oxide (iNO) is known to be elevated in IBD mucosa. SAMP1/YitFc (SAMP1) mouse is a spontaneous model of chronic ileitis that develops lesions in its terminal ileum, very similar to human IBD. How SGLT1 may be affected in SAMP1 model of chronic ileitis is unknown. Ten-week-old SAMP1 mice with AKR mice as control were treated with N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL) to inhibit iNO production. Intracellular NO levels were found to be increased in villus cells from SAMP1 mice. Moreover, SGLT1 and Na+/K+-ATPase activities and BBM SGLT1 expression were significantly decreased. However, L-NIL treatment reduced the intracellular iNO production, and reversed both downregulated SGLT1 and Na+/K+-ATPase activities in SAMP1 mice. Inhibition of iNO by L-NIL treatment also significantly reversed the BBM SGLT1 protein expression in SAMP1 mice. L-NIL reversed the inflammation mediated downregulation of SGLT1 activity by restoring the BBM SGLT1 expression. Thus, regulation of SGLT1 in chronic ileitis is likely mediated by iNO.

scholarly journals Unique Regulation of Intestinal Villus Epithelial Cl−/HCO3− Exchange by Cyclooxygenase Pathway Metabolites of Arachidonic Acid in a Mouse Model of Spontaneous Ileitis

2021 ◽  
Vol 22 (8) ◽  
pp. 4171
Author(s):  
M Motiur Rahman ◽  
Alip Borthakur ◽  
Sheuli Afroz ◽  
Subha Arthur ◽  
Uma Sundaram
Keyword(s):  
Arachidonic Acid ◽  
Brush Border Membrane ◽  
Kinetic Studies ◽  
Intestinal Villus ◽  
Protein Levels ◽  
Nacl Absorption ◽  
Anion Transporter ◽  
Villus Cell ◽  
Acid Metabolites ◽  
Inflammatory Bowel

Electrolytes (NaCl) and fluid malabsorption cause diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption, mediated by Na+/H+ and Cl−/HCO3− exchanges on the intestinal villus cells brush border membrane (BBM), is inhibited in IBD. Arachidonic acid metabolites (AAMs) formed via cyclooxygenase (COX) or lipoxygenase (LOX) pathways are elevated in IBD. However, their effects on NaCl absorption are not known. We treated SAMP1/YitFc (SAMP1) mice, a model of spontaneous ileitis resembling human IBD, with Arachidonyl Trifluoro Methylketone (ATMK, AAM inhibitor), or with piroxicam or MK-886, to inhibit COX or LOX pathways, respectively. Cl−/HCO3− exchange, measured as DIDS-sensitive 36Cl uptake, was significantly inhibited in villus cells and BBM vesicles of SAMP1 mice compared to AKR/J controls, an effect reversed by ATMK. Piroxicam, but not MK-886, also reversed the inhibition. Kinetic studies showed that inhibition was secondary to altered Km with no effects on Vmax. Whole cell or BBM protein levels of Down-Regulated in Adenoma (SLC26A3) and putative anion transporter-1 (SLC26A6), the two key BBM Cl−/HCO3− exchangers, were unaltered. Thus, inhibition of villus cell Cl−/HCO3− exchange by COX pathway AAMs, such as prostaglandins, via reducing the affinity of the exchanger for Cl−, and thereby causing NaCl malabsorption, could significantly contribute to IBD-associated diarrhea.

Cytochemical analysis of mast cell granules after poly-dl-lysine action

1978 ◽  
Vol 36 (2) ◽  
pp. 278-279
Author(s):  
R. Courtoy ◽  
L.J. Simar ◽  
J. Christophe
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Chemical Compounds ◽  
Cellular Membrane ◽  
Thin Sections ◽  
Organic Bases ◽  
Ferric Thiocyanate ◽  
Cytochemical Analysis ◽  
Mast Cell Granule ◽  
Amine Liberation

Several chemical compounds induce amine liberation from mast cells but do not necessarily provoque the granule expulsion. For example, poly-dl-lysine induces modifications of the cellular membrane permeability which promotes ion exchange at the level of mast cell granules. Few of them are expulsed but the majority remains in the cytoplasm and appears less dense to the electrons. A cytochemical analysis has been performed to determine the composition of these granules after the polylysine action.We have previously reported that it was possible to demonstrate polyanions on epon thin sections using a cetylpyridinium ferric thiocyanate method. Organic bases are selectively stained with cobalt thiocyanate and the sulfhydryle groups are characterized with a silver methenamine reaction. These techniques permit to reveal the mast cell granule constituents, i.e. heparin, biogenic amines and basic proteins.

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