Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mast cells and basophils, although sharing many constitutive properties, are quite distinct in their development, functions and biological properties. Mast cell granules are composed of a macromolecular matrix of proteoglycan and neutral protease of which heparin and tryptase, respectively, are predominant. The distribution of the other major neutral protease, chymase, allows human mast cell subpopulations to be subdivided immunocytochemically. All human mast cells respond to IgE-dependent stimulation with the secretion of the preformed mediator, histamine, and the newly generated lipid-derived eicosanoids PGD2 and LTC4. Although amounts of these products vary between mast cells dispersed from different tissues, it is uncertain whether this reflects true heterogeneity. Mast cells of the human skin, but not those of other tissues, are sensitive to stimulation by substance P, compound 48/80 and other basic non-immunological stimuli. The mechanism of mediator secretion induced by these agents is distinct from that induced by IgE-dependent stimulation. However, the morphological characteristics of degranulation are similar, suggesting that the distinct biochemical pathways merge into a common pathway before effecting degranulation.
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PMID:Biological properties of human skin mast cells. 191 78

A long-term co-culture of mononuclear cells of human umbilical cord blood with mouse embryo-derived 3T3 fibroblasts resulted in the development of human mast cells. These mast cells are morphologically and functionally mature cells, containing 1.4-2.8 micrograms histamine per 10(6) cells and bear approximately 10(5) Fc epsilon RI per cell. The mast cells sensitized with human IgE released histamine upon challenge with anti-IgE. Electron-microscopic analysis of the cells showed that these cells were mature human mast cells, and clearly different from basophilic granulocytes. Most of the mast cells contained some granules with regular crystalline arrays and both tryptase and chymase, resembling human skin mast cells. When mononuclear cells of cord blood were seeded in a millicell insert which was placed on 3T3 fibroblasts monolayer, the number of mast cells developed in the millicell inserts was comparable to those developed in the co-culture of the same cord blood cells with 3T3 fibroblasts. Recent observations that mast cells developed in the presence of concentrated culture supernatants of 3T3 fibroblasts without fibroblasts feeder layers, confirmed that soluble factors released from 3T3 fibroblasts are essential and sufficient for the differentiation of human mast cell progenitors in vitro. Analysis of functional characteristics of cultured mast cells revealed that they respond to anti-IgE, Ca2+ ionophore A23187 and substance P for histamine release, but failed to respond to compound 48/80 and FMLP. Upon anti-IgE challenge, sensitized mast cells generated approximately 80 ng PGD2 per 10(6) cells, and approximately 50 ng of LTC4 per 10(6) cells but no detectable generation of LTB4.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro development and functions of human mast cells. 193 64

The peptides substance P (SP) and vasoactive intestinal peptide (VIP) released from peptidergic neurons have potent effects on gland secretion and on smooth muscle tone. Because mast cells release proteases during degranulation, and are located in many of the same tissue microenvironments into which SP and VIP are released, we wished to examine whether mast cell proteases, by cleaving and thus inactivating these peptides, could modulate their effects. We used active site-titrated preparations of the two major neutral proteases of mast cell granules, tryptase and chymase, to determine the sites and rates of cleavage of SP and VIP. The proteases were purified from dog mastocytomas. Tryptase cleaved VIP rapidly at two sites with a kcat/Km of 2.2 X 10(5) sec-1 M-1, but had no effect on SP. Chymase cleaved both SP and VIP at primarily a single site with kcat/Km of 3.9 X 10(4) and 5.4 X 10(4) sec-1 M-1, respectively. Thus, these data show that mast cell proteases degrade SP and VIP. The differences in peptidase activity between tryptase and chymase suggest that the consequences of protease release could vary according to mast cell protease phenotype and location in various tissues and species. Tryptase, by cleaving the bronchodilator VIP but not the bronchoconstrictor SP, might promote bronchial hyper-responsiveness in asthma by decreasing the nonadrenergic neural inhibitory influence mediated by VIP. In skin and other tissues, chymase might interrupt axon reflex-mediated neurogenic inflammation by cleaving SP.
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PMID:Substance P and vasoactive intestinal peptide degradation by mast cell tryptase and chymase. 244 73

We have isolated and characterized the human cardiac mast cell (CMC) and compared this novel mast cell (MC type with MC obtained from uterus, skin, and lung. Heart tissue was obtained from 14 patients with cardiomyopathy (CMP, heart transplantation). CMC were isolated by enzymatic digestion using collagenase, pronase-E, hyaluronidase, and DNAse. Substantial amounts of CMC (0.5% to 1.5% of isolated cells) were found in the atrial appendages but not in ventricular digests or other sites of the heart (< 0.1%). In situ staining of atrial tissue revealed the presence of CMC in the myocardium (2.16 +/- 0.7 MC/mm2), endocardium (2.24 +/- 0.9 MC/mm2), and epicardium. As assessed by combined toluidine blue/immunofluorescence staining with monoclonal antibodies (MoAbs), isolated CMC expressed surface IgE, the receptor for stem cell factor (c-kit receptor/CD117), the p24 antigen (CD9), the Pgp-1 homing receptor (CD44), the pan leukocyte antigen (CD45), and the ICAM-1 antigen (CD54). CMC were not recognized by MoAbs to lymphocyte function associated antigen 2 (LFA-2; CD2), T-cell receptor (TcR; CD3), T4 antigen (CD4), LFA-1 alpha-chain (CD11a), C3biR alpha-chain (CD11b), CR4 alpha-chain (CD11c), LPS-R related Ag (CD14), 3-FAL/x-hapten (CD15), Fc gamma RIII (CD16), lactosylceramid (CDw17), the B-cell antigen CD19, or CR1 (CD35). In situ expression of leukocyte antigens on CMC was demonstrable by indirect immunoperoxidase staining technique and double-labeling immunohistochemistry. Almost all CMC (90%) reacted with MoAbs against tryptase and chymase and thus were MCTC. Cardiac mast cells were also stained by the heparin-binding dye Berberine sulfate and expressed measurable amounts of histamine (4.6 +/- 1.4 pg per cell). Cross linking of either IgE receptor or SCF receptor (c-kit) on CMC resulted in histamine secretion (non-specific release: < 6% of total histamine, alpha IgE induced: 12% to 52%; SCF-induced release: 9% to 18%), whereas neither substance P (a skin MC agonist) nor the basophil agonist FMLP showed an effect on CMC. Together, the CMC is an MCTC primarily located in the appendage of the atrium. This novel type of MC exhibits surface membrane antigen and functional properties similar to those of lung and uterus MC.
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PMID:The human cardiac mast cell: localization, isolation, phenotype, and functional characterization. 752 50

We have isolated, partially purified, and characterized the mast cells from human heart tissue. The histamine content of left and right ventricles and septum of hearts obtained from 25 patients undergoing heart transplantation was 5.4 +/- 0.6, 5.3 +/- 0.5, and 5.6 +/- 0.5 micrograms/g of wet tissue, respectively. Ultrastructural study of cardiac mast cells revealed scroll, crystal, and mixed granules, homogeneously dense granules, and lipid bodies in the cytoplasm. A mild collagenase digestion was used to disperse the heart mast cells; the average yield was 3.2 +/- 0.6% (range: 0.8 to 13.6%). The average histamine and tryptase content/heart mast cells was 3.3 +/- 0.2 pg (n = 25) and 24.2 +/- 4.3 micrograms/10(6) cells (n = 11), respectively. Survival of cardiac mast cells after overnight culture was 71.9 +/- 5.4% (n = 23). The purification of human heart mast cells can be brought from less than 0.1 to 12% by a combination of low-speed centrifugation over albumin (2%) solution and Percoll gradient. Viability as shown by trypan blue exclusion was greater than 90%. Heart mast cells released histamine in response to immunologic (anti-IgE, anti-Fc epsilon RI, and C5a) and nonimmunologic stimuli (recombinant human stem cell factor, A23187, and compound 48/80) but did not respond to substance P, FMLP, 12-O-tetradecanoylphorbol-13-acetate, or acetylcholine. There was a linear correlation between the percentage of release caused by anti-IgE and anti-Fc epsilon RI, whereas there was no correlation between the release caused by C5a and anti-IgE-mediated stimuli. Cross-linking with anti-IgE of IgE on heart mast cells induced the release of tryptase (10.1 +/- 2.1 micrograms/10(7) cells; n = 10) and the de novo synthesis of PGD2 (17.3 +/- 4.3 ng/10(6) cells; n = 10) and of leukotriene C4 (19.1 +/- 4.5 ng/10(6) cells; n = 10). There was a linear correlation between the percentage of histamine secretion and tryptase release (r = 0.67; p < 0.001) induced by cross-linking of Fc epsilon RI. similarly, there was a significant correlation between percentage of histamine secretion and PGD2 (r = 0.63; p < 0.001) and LTC4 (r = 0.64; p < 0.001) release. Immunoelectron microscopy demonstrated the presence of chymase in cardiac mast cells. Mast cells isolated from human heart can be a useful model with which to study the role of these cells and their mediators in cardiac anaphylaxis and cardiovascular diseases.
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PMID:Human heart mast cells. Isolation, purification, ultrastructure, and immunologic characterization. 753 85

All sections of human heart tissue demonstrate tryptase- and chymase-containing mast cells (HHMCs) which have for the first time been isolated, partially purified and studied in vitro. HHMCs contain similar histamine levels as lung and skin mast cells, but tryptase levels are lower than in skin and higher than in lung mast cells. Complement C5a causes rapid dose-dependent release of histamine from HHMCs, but they are refractory to substance P and fMLP. Cross-linking IgE receptors on HHMCs leads to arachidonic acid metabolism through both the cyclooxygenase and 5-lipoxygenase pathways. HHMCs and their vasoactive mediators may be involved in anaphylactic/anaphylactoid reactions in humans and in the pathogenesis of some cardiovascular diseases.
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PMID:Human heart mast cells in anaphylaxis and cardiovascular disease. 754 6

Stress is known to precipitate or worsen a number of disorders, such as migraines, in which mast cells are suspected of being involved by releasing vasoactive, nociceptive, and proinflammatory mediators. However, no functional association has been demonstrated yet between a migraine trigger and brain mast cell activation. Nontraumatic immobilization (restrain) stress has been shown to stimulate the hypothalamic-pituitary-adrenal axis and to cause redistribution of immune cells. Here, restrain stress caused degranulation in 70% of rat dura mast cells within 30 min, as shown both by light and electron microscopy. These morphologic findings were accompanied by cerebrospinal fluid elevation of rat mast cell protease I, but not II, indicating secretion from connective tissue type mast cells. Mast cell activation due to stress was abolished in animals that had been treated neonatally with capsaicin, indicating that neuropeptides in sensory nerve endings are involved in this response. Complete inhibition was also achieved by pretreating the animals ip with polyclonal antiserum to CRH. Mast cells in the dura were localized close to nerve processes containing substance P, but no CRH-positive fibers were identified even though these were found close to mast cells in the median eminence. This is the first time that stress is shown to activate intracranial mast cells; apparently through the sequential action of CRH and sensory neuropeptides. These findings may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders such as migraines, which are induced or exacerbated by stress.
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PMID:Stress-induced intracranial mast cell degranulation: a corticotropin-releasing hormone-mediated effect. 758 32

Media conditioned by compound 48/80-stimulated rat mast cells generated immunoreactive histamine-releasing peptide (HRP) when incubated at physiological pH with bovine serum albumin and the carboxypeptidase inhibitor, O-phenanthroline. The generation of immunoreactive HRP (IR-HRP) was time (after 3 h the concentration of IR-HRP was 20 nM), temperature, and pH dependent and was prevented by omitting albumin, by using media conditioned by nonstimulated mast cells, or by pretreatment of mast cells with disodium cromoglycate, an inhibitor of mast cell secretion. The amount of IR-HRP generated increased linearly with the number of mast cells stimulated and varied directly with the concentration of conditioned media. After removal of the media from stimulated mast cells, the remaining cell pellet retained its ability to generate IR-HRP for up to 8 h. Stimulation of mast cells by either neurotensin or substance P, or of sensitized cells by anti-IgE serum, also produced conditioned media that generated IR-HRP. The amount of IR-HRP formed by various conditioned media or by stimulated cell pellets was dependent upon the concentration of O-phenanthroline used. Including the chymase inhibitor, chymostatin, prevented the formation of IR-HRP in a dose-dependent manner. HPLC analysis showed four peaks of IR-HRP. The major one coeluted with synthetic HRP. These results indicate that the peptide, HRP, can be generated by stimulated mast cells incubated in the presence of albumin. They suggest that a chymase-like enzyme secreted by the mast cell is able to cleave albumin to yield HRP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulated rat mast cells generate histamine-releasing peptide from albumin. 768 97

Association of stress with psoriatic skin symptoms was studied in 13 patients with psoriasis by dividing the patients into low- and high-stress groups based on their clinical examination and answers to three questionnaires (General Health Questionnaire, a somatization scale, and a life change questionnaire). This study focused on skin mast cells and sensory nerves which are the principal components in neurogenic inflammation. Mast cells were stained enzyme-histochemically for tryptase and chymase, and neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), and calcitonin gene-related peptide (CGRP) were demonstrated immunohistochemically. Compared to the low-stress group (n = 7), the patients in the high-stress group (n = 6) had more severe skin and joint symptoms. Furthermore, mast cells positive for chymase activity were prominently reduced, but tryptase-positive mast cells only slightly decreased in the lesional skin of the high-stress group. A similar tendency was also observed in the nonlesional skin. In the papillary dermis of the lesional skin, both VIP- and CGRP-immunoreactive nerves could be observed in the high-stress group whereas in the low-stress group these nerve fibers were hardly visible in the corresponding area. No association of SP with stress was observed. This study suggests that psychic stress is associated with exacerbation of psoriasis, and stress may induce alterations in the psoriatic lesions by increasing the neuropeptide content with a concomitant decrease in the activity of neuropeptide-degrading enzymes, especially mast cell chymase.
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PMID:Association of cutaneous mast cells and sensory nerves with psychic stress in psoriasis. 827 75

In this study, we have characterized the phenotype of mast cells in rat dura mater and their topological and functional relationships with C-fibers in normal and inflammatory conditions. Three mast cell populations with different size, morphology and localization were characterized by their content of specific neutral serine proteases. They showed immunoreactivity corresponding to rat mast cell protease I, rat mast cell protease II, or both proteases. Using confocal microscopy, all three mast cell types were observed in close apposition (distance less than 100 nm) to calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in both controls and rats infected with the nematode Nippostrongylus brasiliensis. After nematode infection or neonatal treatment with capsaicin, a large increase in the number of rat mast cell protease II-immunoreactive mast cells was found within dura mater segments (+1478% and +596%, respectively), without concomitant changes of rat mast cell protease I- or rat mast cell protease I/II-immunoreactive mast cells. Under both these conditions, the increase in mast cell number was accompanied by a significant increase in rat mast cell protease II level within tissue extracts (+281% after nematode infection and +36% after capsaicin treatment). The functional interaction of mast cells with sensory nerve fibers in the dura mater was assessed by evaluating [3H]histamine synthesis after administration of L-[3H]histidine, an index of mast cell activity. The H3 receptor agonist (R)-alpha-methylhistamine (15 mg/kg, i.p.) had no effect, but administration of the H3 receptor antagonist, thioperamide (10 mg/kg, i.p.), resulted in a significant increase of [3H]histamine synthesis (+62%). This effect was reduced in neonatal capsaicin-treated rats, but not completely suppressed (+35%), very likely because of partial denervation, as assessed by monitoring calcitonin gene-related peptide immunoreactivity. It is concluded that, in the dura mater, as in peripheral tissues, sensory nerve fibers and mast cells actively synthesizing and releasing histamine form a short inhibitory feedback loop involving prejunctional H3 receptors that could regulate the release of pro-inflammatory mediators, thus limiting the extent of inflammatory reactions.
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PMID:Functional relationships between sensory nerve fibers and mast cells of dura mater in normal and inflammatory conditions. 907 Jul 55


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