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Michael Thorpe, Zhirong Fu, Emanuelle Albat, Srinivas Akula, Lawrence de Garavilla, Jukka Kervinen, Lars Hellman
Serine proteases constitute the major protein content of mast cell secretory granules. Here we present the extended cleavage specificity of two such proteases from the golden hamster, Mesocricetus auratus. Analysis by phage display technique showed that one of them (HAM1) is a classical chymase with a specificity similar to the human mast cell chymase. However, in contrast to the human chymase, it does not seem to have a particular preference for any of the three aromatic amino acids, Phe, Tyr and Trp, in the P1 position of substrates...
2018: PloS One
Flavie Ngo Nyekel, Emeline Pacreau, Samira Benadda, Rasha Msallam, Magnus Åbrink, Gunnar Pejler, Jean Davoust, Marc Benhamou, Nicolas Charles, Pierre Launay, Ulrich Blank, Gregory Gautier
Recent evidences indicate an important role of tissue inflammatory responses by innate immune cells in allograft acceptance and survival. Here we investigated the role of mast cells (MC) in an acute male to female skin allograft rejection model using red MC and basophil (RMB) mice enabling conditional MC depletion. Kinetic analysis showed that MCs markedly accelerate skin rejection. They induced an early inflammatory response through degranulation and boosted local synthesis of KC, MIP-2, and TNF. This enhanced early neutrophil infiltration compared to a female-female graft-associated repair response...
2018: Frontiers in Immunology
Daniel Elieh Ali Komi, Leif Bjermer
Improving the lung function after experimental allergen challenge by blocking of mast cell (MC) mediators and the capability of MC mediators (including histamine, prostaglandin (PG) D2, and leukotriene (LT) C4) in induction of mucosal edema, bronchoconstriction, and mucus secretion provide evidence that MCs play a key role in pathophysiology of asthma. In asthma, the number of MCs increases in the airways and infiltration of MCs in a variety of anatomical sites including the epithelium, the submucosal glands, and the smooth muscle bundles occurs...
November 30, 2018: Clinical Reviews in Allergy & Immunology
Zhirong Fu, Srinivas Akula, Michael Thorpe, Gurdeep Chahal, Lawrence de Garavilla, Jukka Kervinen, Lars Hellman
Serine proteases constitute the major protein content of mammalian mast cell granules and the selectivity for substrates by these proteases is of major importance for the role of mast cells in immunity. In order to address this subject, we present here the extended cleavage specificity of sheep mast cell protease-2 (MCP2), a chymotrypsin-type serine protease. Comparison of the extended specificity results to a panel of mammalian mast cell chymases show, in almost all aspects, the same cleavage characteristics...
November 24, 2018: Developmental and Comparative Immunology
Arnar Bragi Ingason, Fatich Mechmet, Diahann Alexandra Maria Atacho, Eiríkur Steingrímsson, Pétur Henry Petersen
Although mast cell distribution has been described in both human and canine hearts, cardiac mast cells in mice have yet to be categorically localized. We therefore sought to describe mast cell distribution within the mouse heart and characterize their dependence on the Microphthalmia-associated transcription factor (Mitf). Cardiac mast cells were visualized using Toluidine Blue and avidin staining, and their distribution within the heart described. Cardiac mast cells were most prevalent in the epicardium (50%) or myocardium (45%)...
November 21, 2018: Molecular Immunology
Anne Dudeck, Martin Köberle, Oliver Goldmann, Nicole Meyer, Jan Dudeck, Stefanie Lemmens, Manfred Rohde, Nestor González Roldán, Kirsten Dietze-Schwonberg, Zane Orinska, Eva Medina, Sven Hendrix, Martin Metz, Ana Claudia Zenclussen, Esther von Stebut, Tilo Biedermann
Mast cells (MC), well known for their effector functions in Th2 skewed allergic and also autoimmune inflammation, become increasingly acknowledged for their role in protection of health. It is now clear that they are also key modulators of immune responses at interface organs like skin or gut. MC can prime tissues for adequate inflammatory responses and cooperate with dendritic cells in T cell activation. They also regulate harmful immune responses in trauma and help to successfully orchestrate pregnancy. This review focusses on the beneficial effects of mast cells on tissue homeostasis and elimination of toxins or venoms...
November 20, 2018: Journal of Allergy and Clinical Immunology
Jingyi Liu, Zhirong Fu, Lars Hellman, Staffan G Svärd
Giardia intestinalis is a protozoan parasite and the causative agent of giardiasis, a common diarrheal disease. Cysteine protease (CP) activities have been suggested to be involved in Giardia's pathogenesis and we have recently identified and characterized three secreted Giardia CPs; CP14019, CP16160 and CP16779. Here we have studied the cleavage specificity of these CPs using substrate phage display and recombinant protein substrates. The phage display analyses showed that CP16160 has both chymase and tryptase activity and a broad substrate specificity...
November 17, 2018: Molecular and Biochemical Parasitology
Hans-Dirk Düngen, Lars Kober, Savina Nodari, Morten Schou, Christiane Otto, Michael Becka, Friederike Kanefendt, Bernhard R Winkelmann, Gunnar Gislason, Frank Richard, Olav Wendelboe Nielsen, Mihai Gheorghiade, Michele Senni
The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose...
November 19, 2018: Clinical Pharmacology in Drug Development
Jenny Paupert, Eric Espinosa, Nicolas Cenac, Virginie Robert, Patrick Laharrague, Solène M Evrard, Louis Casteilla, Anne Lorsignol, Béatrice Cousin
Mast cells (MC) are innate immune cells involved in many physiological and pathological processes. However, studies of MC function and biology are hampered by the difficulties to obtain human primary MC. To solve this problem, we established a new method to produce easily and rapidly high numbers of MC for in vitro studies using human adipose tissue, which is an abundant and easy access tissue. Stromal vascular fraction of adipose tissue, obtained from human abdominal dermolipectomy, was cultured as spheroids in serum free medium supplemented in stem cell factor...
November 16, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Xiaoying Zhou, Tao Wei, Christopher W Cox, Andrew F Walls, Yuan Jiang, William R Roche
BACKGROUND: An increased degree of mast cell (MC) degranulation and damage to the epithelial lining are prominent features of bronchial asthma. In asthmatic airways, it seems likely that epithelial cells will be exposed to increased concentrations of proteases from MC, though their actions on the epithelium are still not very clear. METHODS: Bronchial rings from human lung tissue or 16HBE cell monolayer were incubated with MC-chymase in different doses or various inhibitors...
November 14, 2018: Allergy
Francielle Beltrão Pereira, Walderez O Dutra, Kenneth J Gollob, Edna Afonso Reis, Ana Laura Grossi de Oliveira, Manoel Otávio da Costa Rocha, Cristiane Alves da Silva Menezes
The vasoactive intestinal peptide (VIP) expression is lower in cardiac chagasic patients and is related to worse cardiac function. The reduction of VIP in patients with Chagas disease may be a result of its enhanced degradation. To test this hypothesis, the tryptase and chymase expression was evaluated. We also related VIP levels with interleukin-17 (IL-17) expression since VIP may modulate IL-17 production. Plasma levels of chymase were higher in chagasic patients. Conversely, VIP/chymase and VIP/tryptase ratios were lower in chagasic patients when compared to non-infected individuals...
October 22, 2018: Revista do Instituto de Medicina Tropical de São Paulo
Rodrigo Yokota, Fernanda Aparecida Ronchi, Fernanda Barrinha Fernandes, Zaira Palomino Jara, Rodolfo Mattar Rosa, Ana Paula de Oliveira Leite, Patricia Fiorino, Vera Farah, Nilberto Robson Falcão do Nascimento, Manassés C Fonteles, Dulce Elena Casarini
Overconsumption of fructose leads to metabolic syndrome as a result of hypertension, insulin resistance, and hyperlipidemia. In this study, the renal function of animals submitted to high fructose intake was analyzed from weaning to adulthood using in vivo and ex vivo methods, being compared with a normal control group. We investigated in ex vivo model of the role of the renin Angiotensin system (RAS) in the kidney. The use of perfused kidney from animals submitted to 8-week fructose treatment showed that high fructose intake caused metabolic and cardiovascular alterations that were consistent with other studies...
2018: Frontiers in Physiology
Yuebo Zhang, Kiran R Somers, Christiane Becari, Katarzyna Polonis, Michaela A Pfeifer, Alina M Allen, Todd A Kellogg, Naima Covassin, Prachi Singh
Body fat distribution contributes to obesity-related metabolic and cardiovascular disorders. Visceral fat is more detrimental than subcutaneous fat. However, the mechanisms underlying visceral fat-mediated cardiometabolic dysregulation are not completely understood. Localized increases in expression of the renin angiotensin system (RAS) in adipose tissue (AT) may be implicated. We therefore investigated mRNA and protein expression of RAS components in visceral versus subcutaneous AT using paired samples from individuals undergoing surgery ( N = 20, body mass index: 45...
2018: Frontiers in Physiology
Avinash Ravindran, Elin Rönnberg, Joakim S Dahlin, Luca Mazzurana, Jesper Säfholm, Ann-Charlotte Orre, Mamdoh Al-Ameri, Peter Peachell, Mikael Adner, Sven-Erik Dahlén, Jenny Mjösberg, Gunnar Nilsson
Background: Mast cells are tissue-resident inflammatory cells defined by their high granularity and surface expression of the high-affinity IgE receptor, FcεRI, and CD117/KIT, the receptor for stem cell factor (SCF). There is a considerable heterogeneity among mast cells, both phenotypically and functionally. Human mast cells are generally divided into two main subtypes based on their protease content; the mucosa-associated MCT (tryptase positive and chymase negative mast cell) and the connective tissue associated-residing MCTC (tryptase and chymase positive mast cell)...
2018: Frontiers in Immunology
Weifeng Yuan, Shaohua Hou, Hong Jia, Zhizhao Qiu, Tao Liu, Xinsheng Chen, Hongjun Li, Yanchen Sun, Lin Liang, Xiukun Sui, Xinghui Zhao, Zhanzhong Zhao
Gingivitis is evidenced by inflammation of the free gingiva, and still reversible. If left untreated, it may then progress to periodontitis. In the present study, the therapeutical effect of ketotifen fumarate on gingivitis was explored. Domestic cats with varying degrees of gingivitis naturally were enrolled in this study. Subgroups of animals were treated twice daily for one week with or without ketotifen fumarate (5 mg/kg). Effects of ketotifen fumarate were measured on gingival index, cells accumulation, mediators release, receptor-ligand interaction, oxidative stress, MAPK and NF-κB pathways, epithelial barrier and apoptosis...
December 2018: International Immunopharmacology
Mariyana Hristova, Spaska Stanilova, Lyuba Miteva
BACKGROUND: Renin-angiotensin system (RAS) is a complex network of enzymes and peptides with the essential role in blood pressure control. The relationships between RAS components, RAS-related genetic polymorphisms and therapy response in essential hypertension (EH) were widely explored but the results were inconclusive. AIM: The aim of this study was to explore the functional role of ACE insertion/deletion (I/D) polymorphism on the systemic quantity of angiotensin-converting enzyme (ACE), its homolog - ACE2, chymase and angiotensin II in EH patients with respect to achieved therapeutic blood pressure control...
October 11, 2018: Clinical and Experimental Hypertension: CHE
Nicholas G Kounis, Gianfranco Cervellin, Ioanna Koniari, Laura Bonfanti, Periklis Dousdampanis, Nikolaos Charokopos, Stelios F Assimakopoulos, Stavros K Kakkos, Ioannis G Ntouvas, George D Soufras, Ioannis Tsolakis
The first reported human anaphylactic death is considered to be the Pharaoh Menes death, caused by a wasp sting. Currently, anaphylactic cardiovascular events represent one of most frequent medical emergencies. Rapid diagnosis, prompt and appropriate treatment can be life saving. The main concept beyond anaphylaxis lies to myocardial damage and ventricular dysfunction, thus resulting in cardiovascular collapse. Cardiac output depression due to coronary hypoperfusion from systemic vasodilation, leakage of plasma and volume loss due to increased vascular permeability, as well as reduced venous return, are regarded as the main causes of cardiovascular collapse...
September 2018: Annals of Translational Medicine
S M Pilkington, M J Barron, R E B Watson, C E M Griffiths, S Bulfone-Paus
BACKGROUND: Skin health declines with age and this is partially attributed to immunosenescence. Mast cells (MCs) are innate immune cells which coordinate tissue immune responses integral to skin homeostasis and disease. OBJECTIVES: To understand how MCs contribute to human skin ageing, we investigated how intrinsic ageing impacts MC phenotype and MC relationships with other immune cells and skin structures. METHODS: In photoprotected skin biopsies from young (≤30yrs) and aged (≥75yrs) individuals immunostaining and spatial morphometry were performed to identify changes in MC phenotype, number, distribution and interaction with the vasculature and nerve fibres...
October 6, 2018: British Journal of Dermatology
Sarfaraz Ahmad, Carlos M Ferrario
Chymase is primarily found in mast cells (MCs), fibroblasts, and vascular endothelial cells. MC chymase is released into the extracellular interstitium in response to inflammatory signals, tissue injury, and cellular stress. Among many functions, chymase is a major extravascular source for angiotensin II (Ang II) generation. Several recent pre-clinical and a few clinical studies point to the relatively unrecognized fact that chymase inhibition may have significant therapeutic advantages over other treatments in halting progression of cardiac and vascular disease...
November 2018: Expert Opinion on Therapeutic Patents
Martin Houde, Adel Schwertani, Hanène Touil, Louisane Desbiens, Otman Sarrhini, Roger Lecomte, Martin Lepage, Hugo Gagnon, Shinji Takai, Gunnar Pejler, Danielle Jacques, Fernand Gobeil, Robert Day, Pedro D'Orléans-Juste
Chymase, a mast cell serine protease involved in the generation of multiple cardiovascular factors, such as angiotensin II and endothelin-1 (ET-1), is elevated and participates in tissue degeneration after permanent myocardial infarction (PMI). Anesthetized 4-month old male wild-type (WT) C57BL/6J mice and mouse mast cell protease-4 knockout (mMCP-4 KO) congeners were subjected to ligation of the left anterior descending (LAD) coronary artery. A group of mice was then subjected to Kaplan-Meier 28-day survival analysis...
2018: Frontiers in Pharmacology
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