Effect of mast cell stabilization on angiogenesis in primary and secondary experimental Trichinella spiralis infection

Abstract Background Mast cells are known to affect the primary and secondary immune responses against parasites, and this effect is partially mediated through the release of pro-angiogenic mediators. The aim of this study was to explore the effect of the mast cell stabilizer (MCS), ketotifen, with and without albendazole, an anti-parasitic prescription medicine, on the inflammatory response against Trichinella spiralis, with the overall aim to investigate its effect on angiogenesis accompanying nurse cell formation. Methods The effect of ketotifen and albendazole was explored in eight groups of female BALB/c mice. Four groups were sensitized with a small dose of T. spiralis larvae. The drug regimen was then applied to both sensitized (challenged) and non-sensitized mice. The parasite load was assessed by histopathological examination of the small intestine and muscle tissue, and angiogenesis was assessed by immunohistochemistry to determine the expression of vascular endothelial growth factor (VEGF). Results Sensitized mice showed a significantly lower parasite load and a more pronounced inflammatory response than mice receiving a single infective dose of T. spiralis larvae. All treated groups showed a significant reduction in parasite count compared to the control groups (groups IAa and IBa), reaching approximately an 98.8% reduction in adult parasite count in the sensitized group treated with albendazole (groups IIAb and IIBb). MCS significantly decreased the parasite count during both the intestinal or muscular phases, reduced tissue inflammation, and decreased local VEGF expression, both in the non-sensitized and sensitized groups. Conclusion Sensitization with a low dose of T. spiralis larvae was found to confer a partial protective immunity against re-infection and to positively affect the study outcomes, thus underlining the importance of vaccination, but after extensive studies. The anti-angiogenic effect of MCS protects against larval encystation during the muscle phase. The anti-angiogenic potential of albendazole suggests that the action of this anti-helminthic during trichinellosis is not confined to structural damage to the parasite cuticle but includes an effect on host immunopathological response. Graphical Abstract

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Small intestinal motor and inflammatory response to in vivo localized mast cell degranulatiqn by compound 48/80

Gastroenterology ◽

10.1016/0016-5085(94)90272-0 ◽

1994 ◽

Vol 107 (4) ◽

pp. 1219

Author(s):

S. Graf ◽

S.K. Sarna ◽

J. Fink

Keyword(s):

Mast Cell ◽

Inflammatory Response ◽

Small Intestinal

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Mast cell mediated inflammatory response in chickens after infection with very virulent infectious bursal disease virus

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2008.01.005 ◽

2008 ◽

Vol 124 (1-2) ◽

pp. 19-28 ◽

Cited By ~ 26

Author(s):

Decheng Wang ◽

Jinmao Xiong ◽

Ruiping She ◽

Liqiang Liu ◽

Yanmei Zhang ◽

...

Keyword(s):

Mast Cell ◽

Inflammatory Response ◽

Disease Virus ◽

Infectious Bursal Disease Virus ◽

Infectious Bursal Disease ◽

Bursal Disease

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Tumor necrosis factor receptor-mediated apoptosis in Trichinella spiralis-infected muscle cells

Parasitology ◽

10.1017/s0031182005007663 ◽

2005 ◽

Vol 131 (3) ◽

pp. 373-381 ◽

Cited By ~ 21

Author(s):

Z. WU ◽

I. NAGANO ◽

T. BOONMARS ◽

Y. TAKAHASHI

Keyword(s):

Caspase 3 ◽

Trichinella Spiralis ◽

Cell Formation ◽

Muscle Cells ◽

Cyst Formation ◽

Signalling Pathway ◽

Tnf Receptor ◽

Tnf Α ◽

Infected Muscle ◽

Necrosis Factor

In order to reveal the mechanisms underlying nurse cell formation during Trichinella spiralis infection, the expression of the factors of tumor necrosis factor-alpha (TNF-α)/TNF receptor 1 (TNFR-1) signalling pathway mediating apoptosis was investigated. The analysed factors included TNF-α, TNFR-1, TNF receptor-associated death-domain (TRADD), caspase 3, caspase 8, TNF receptor associated factor-2 (TRAF2) and receptor interactive protein (RIP), all of which are involved in the TNF-α/TNFR-1 signalling pathway-mediated apoptosis. The quantitative RT-PCR indicated that the infected muscle tissues up-regulate the expression of pro-apoptosis genes (TNF-α, TNFR-1 and TRADD, caspase 3 and caspase 8), and anti-apoptosis genes (TRAF2 and RIP) at the beginning of cyst formation. The expression returned to the normal level after cyst formation. The quantitative RT-PCR analysis of mRNA from tissue samples isolated by laser capture micro-dissection confirmed that the up-regulation of these genes was restricted in infected muscle cells, was not in the inflammation cells around infected muscle cells nor in normal muscle cells. The in situ localization study of pro-apoptosis (TRADD, caspase 3) and anti-apoptosis gene products (TRAF2) indicated that these were expressed in the basophilic cytoplasm (infected muscle cell origin) of the nurse cells. Thus the present study suggests that the TNF-α/TNFR-1 signalling pathway is involved in nurse cell formation.

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Biochemical and immunological characterization of multiple glycoforms of mouse mast cell protease 1: comparison with an isolated murine serosal mast cell protease (MMCP-4)

Biochemical Journal ◽

10.1042/bj2940127 ◽

1993 ◽

Vol 294 (1) ◽

pp. 127-135 ◽

Cited By ~ 21

Author(s):

G F J Newlands ◽

D P Knox ◽

S R Pirie-Shepherd ◽

H R P Miller

Keyword(s):

Mast Cell ◽

Amino Acid ◽

Mast Cells ◽

Western Blotting ◽

Trichinella Spiralis ◽

Double Diffusion ◽

Terminal Amino Acid ◽

Mast Cell Protease ◽

Terminal Amino ◽

Mouse Mast Cell

Five highly soluble, chymotrypsin-like, neutral serine proteases, with molecular masses in the range 30-33 kDa, were isolated from Trichinella spiralis-infected mouse small intestine. These enzymes were closely related antigenically on Western blotting and by Ouchterlony double diffusion using a polyclonal, cross-absorbed, sheep antibody raised against mouse mast cell protease-1 (MMCP-1) and on the basis of N-terminal amino acid sequence analysis, were identified as variant forms of MMCP-1. Substrate and inhibitor analysis confirmed that the five variants (MMCP-1 A-E) had similar characteristics, although highly significant (P = 0.025 to P < 0.0001) variations in Km and kcat, were detected. Against human alpha 1-proteinase inhibitor the Ki for MMCP-1C (45 pM) was significantly (P < 0.0001) greater than those for the other proteases (0.76-2.2 pM). The differences in electrophoretic mobility are probably a result of variable glycosylation, since removal of N-linked carbohydrate produced a polypeptide of approx. 28 kDa in each case which was, like the native enzyme, immunoreactive on Western blotting. A much less soluble 28 kDa enzyme was isolated from serosal mast cells and identified as MMCP-4 by N-terminal amino acid sequencing. Like MMCP-1 it has chymotrypsin-like substrate specificities with activity at neutral pH. However, it was antigenically distinct from MMCP-1 and, using sheep anti-MMCP-1, was not detected on Western blotting or by Ouchterlony double diffusion, e.l.i.s.a. or immunohistochemistry. This last technique established that the MMCP-1 variants were uniquely present in enteric mast cells, thereby providing a highly selective means of distinguishing the mucosal and connective tissue mast cell subsets in the mouse.

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Effects of electrochemotherapy with cisplatin and peritumoral IL-12 gene electrotransfer on canine mast cell tumors: a histopathologic and immunohistochemical study

Radiology and Oncology ◽

10.1515/raon-2017-0035 ◽

2017 ◽

Vol 51 (3) ◽

pp. 286-294 ◽

Cited By ~ 14

Author(s):

Claudia Salvadori ◽

Tanja Svara ◽

Guido Rocchigiani ◽

Francesca Millanta ◽

Darja Pavlin ◽

...

Keyword(s):

Mast Cell ◽

T Lymphocytes ◽

Mhc Class Ii ◽

Cellular Response ◽

Histopathological Examination ◽

Combined Treatment ◽

Gene Electrotransfer ◽

Neoplastic Cells ◽

Ki 67 ◽

Mast Cell Tumors

AbstractBackgroundThe study was aimed to characterize tumor response after combined treatment employing electrochemotherapy with IL-12 gene electrotransfer in dogs with spontaneous mast cell tumors (MCT).Materials and methodsEleven dogs with eleven MCTswere included in the study. Histological changes were investigated in biopsy specimens collected before the treatment (T0), and 4 (T1) and 8 weeks (T2) later. Cellular infiltrates were characterized immunohistochemically by using anti CD3, CD20, Foxp3 (Treg), CD68 and anti MHC-class II antibodies. Proliferation and anti-apoptotic activity of neoplastic cells were assessed using anti Ki-67 and Bcl-2 antibodies. Angiogenetic processes were investigated immunohistochemically by using anti Factor VIII and anti CD31 antibodies and micro vessel density quantification.ResultsHistopathological examination of samples at T0confirmed the diagnosis and the presence of scanty infiltrates consisted mainly of T-lymphocytes and macrophages. At T1and T2neoplastic cells were drastically reduced in 7/11 cases, small clusters of neoplastic cells were detected in 3/11 cases and 1/11 cases neoplastic cells were still evident. Proliferation activity of neoplastic cells was significantly reduced at T1and T2and expression of anti-apoptotic protein at T1. Microvessel density was drastically reduced in all samples after treatment. The number of T-lymphocytes increased at T1, although not significant, while Treg were significant higher at T1and macrophages at T2.ConclusionsThe combined electrochemotherapy and IL-12 gene electrotransfer effectively induced a cellular response against neoplastic cells characterized mainly by the recruitment of T-lymphocytes and macrophages and a fibrotic proliferation with reduction of microvessels.

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Treatment of a feline cutaneous mast cell tumour using imatinib mesylate as a neoadjuvant tyrosine kinase inhibitor therapeutic agent

Veterinární Medicína ◽

10.17221/91/2019-vetmed ◽

2020 ◽

Vol 65 (No. 2) ◽

pp. 84-88

Author(s):

J Kim ◽

HJ Kim

Keyword(s):

Mast Cell ◽

Imatinib Mesylate ◽

Histopathological Examination ◽

The Body ◽

Cell Tumour ◽

Surgical Removal ◽

Anatomical Location ◽

Tumour Mass ◽

Mast Cell Tumour ◽

Cutaneous Mast Cell

A two-year-old spayed female American shorthair cat presented with a rough, circular, exophytic mass on the genital area. The clinical findings and histopathological examination revealed that the mass contained neoplastic mast cells and, thus, was diagnosed as a mast cell tumour. The anatomical location of the mass was not easily accessible for surgical intervention. We administered a targeted therapy using oral imatinib mesylate for eight weeks to reduce the size of the lesion and to facilitate the successful surgical removal. The tumour mass eventually reduced by 21% and was surgically excised. This is possibly the first study to use imatinib mesylate as a tumour reduction neoadjuvant to therapeutically address a feline cutaneous mast cell tumour located in a surgically inaccessible part of the body.

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Role of Phagocytosis in the Pro-Inflammatory Response in LDL-Induced Foam Cell Formation; a Transcriptome Analysis

International Journal of Molecular Sciences ◽

10.3390/ijms21030817 ◽

2020 ◽

Vol 21 (3) ◽

pp. 817 ◽

Cited By ~ 5

Author(s):

Alexander N. Orekhov ◽

Nikita G. Nikiforov ◽

Vasily N. Sukhorukov ◽

Marina V. Kubekina ◽

Igor A. Sobenin ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Master Regulators ◽

Knock Down ◽

Modified Ldl ◽

Naturally Occurring ◽

Stimulation Of

Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that were involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. It was found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary event occurring upon the interaction of modified LDL and macrophages is the stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response. We identified genes that were up- or downregulated following the exposure of cultured cells to modified LDL or latex beads (inert phagocytosis stimulators). Most of the identified master regulators were involved in the innate immune response, and some of them were encoding major pro-inflammatory proteins. The obtained results indicated that pro-inflammatory response to phagocytosis stimulation precedes the accumulation of intracellular lipids and possibly contributes to the formation of foam cells. In this way, the currently recognized hypothesis that the accumulation of lipids triggers the pro-inflammatory response was not confirmed. Comparative analysis of master regulators revealed similarities in the genetic regulation of the interaction of macrophages with naturally occurring LDL and desialylated LDL. Oxidized and desialylated LDL affected a different spectrum of genes than naturally occurring LDL. These observations suggest that desialylation is the most important modification of LDL occurring in vivo. Thus, modified LDL caused the gene regulation characteristic of the stimulation of phagocytosis. Additionally, the knock-down effect of five master regulators, such as IL15, EIF2AK3, F2RL1, TSPYL2, and ANXA1, on intracellular lipid accumulation was tested. We knocked down these genes in primary macrophages derived from human monocytes. The addition of atherogenic naturally occurring LDL caused a significant accumulation of cholesterol in the control cells. The knock-down of the EIF2AK3 and IL15 genes completely prevented cholesterol accumulation in cultured macrophages. The knock-down of the ANXA1 gene caused a further decrease in cholesterol content in cultured macrophages. At the same time, knock-down of F2RL1 and TSPYL2 did not cause an effect. The results obtained allowed us to explain in which way the inflammatory response and the accumulation of cholesterol are related confirming our hypothesis of atherogenesis development based on the following viewpoints: LDL particles undergo atherogenic modifications that, in turn, accompanied by the formation of self-associates; large LDL associates stimulate phagocytosis; as a result of phagocytosis stimulation, pro-inflammatory molecules are secreted; these molecules cause or at least contribute to the accumulation of intracellular cholesterol. Therefore, it became obvious that the primary event in this sequence is not the accumulation of cholesterol but an inflammatory response.

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