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

Mast cells are important effector cells of allergy and techniques for culturing human mast cells have been developed in recent years. In the current investigation, we studied the phenotypic and functional characteristics of mast cells cultured from adult human peripheral blood mononuclear cells. Mature human mast cells were obtained by first culturing mononuclear cells in methylcellulose containing stem cell factor (SCF), IL-3 and IL-6 for six weeks and subsequently in liquid medium containing SCF and IL-6 for another six weeks. These cells expressed numerous basophilic cytoplasmic granules that were predominantly tryptase positive but chymase negative. Following sensitization with human IgE, these cells released histamine and synthesized prostaglandin D2 and cysteinyl-leukotrienes dose-dependently upon activation by anti-IgE and calcium ionophores. Compound 48/80 and substance P were ineffective. When the effects of anti-asthmatic agents on anti-IgE induced mediator release from these cells were compared, only the beta2-adrenoceptor agonists and phosphodiesterase inhibitors produced dose-dependent inhibition but not cromolyn. In total, mast cells cultured from human peripheral blood shared similar morphological, immunocytochemical and functional properties of enzymatically dispersed human lung mast cells. These cultured mast cells can be a convenient substitute for the in vitro studies of human lung mast cell reactions and may be useful for investigating the roles of mast cells in allergic diseases.
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PMID:Functional characterization of human mast cells cultured from adult peripheral blood. 1654 15

Acute pancreatitis in its severe form is complicated by multiple organ system dysfunction, most importantly by pulmonary complications which include hypoxia, acute respiratory distress syndrome, atelectasis, and pleural effusion. The pathogenesis of some of the above complications is attributed to the production of noxious cytokines. Clinically significant is the early onset of pleural effusion, which heralds a poor outcome of acute pancreatitis. The role of circulating trypsin, phospholipase A2, platelet activating factor, release of free fatty acids, chemoattractants such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, IL-8, fMet-leu-phe (a bacterial wall product), nitric oxide, substance P, and macrophage inhibitor factor is currently studied. The hope is that future management of acute pancreatitis with a better understanding of the pathogenesis of lung injury will be directed against the production of noxious cytokines.
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PMID:Pathophysiology of pulmonary complications of acute pancreatitis. 1713 69

Nerve fibers and sensory neuropeptides substance P and calcitonin gene-related peptide (CGRP) have been reported to be involved in allergic contact dermatitis (ACD). In the present study, we investigated the general innervation (using antibody against protein gene product 9.5, PGP 9.5), axonal growth (using antibody against growth associated protein, GAP-43), CGRP, and substance P with its receptor neurokinin 1 (NK1), in positive epicutaneous reactions to nickel sulphate from nickel-allergic patients, at the peak of inflammation, 72 hr after challenge with the antigen. There was an increased (p < 0.01) number of GAP-43 positive fibers in the eczematous compared with control skin, indicating an increased axonal growth already at 72 hr postchallenge. Double staining revealed a coexpression of CGRP and GAP-43 on dermal nerve fibers. There was no difference in the number of substance P and CGRP positive nerve fibers between eczematous and control skin. However, semiquantification analyses showed an increased expression of substance P positive inflammatory cells, being CD3, CD4, or CD8 positive, and NK1R positive inflammatory cells, being tryptase or CD3 positive. These results indicate a contribution of regenerating nerve fibers and substance P to the contact allergic reaction.
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PMID:Upregulation of the axonal growth and the expression of substance P and its NK1 receptor in human allergic contact dermatitis. 1719 Jul 39

Mast cells are unique immune cells that release a spectrum of chemical mediators contributing to the inflammatory symptoms of allergic disorders. Although mast cell biology has been extensively studied in the rodents, research on human mast cells is hampered by the lack of a convenient preparation source. This problem has now been addressed by culturing human mast cells from CD34(+) progenitors. We have recently discovered that human buffy coat preparations from local blood banks are an abundant and convenient source of progenitors for culturing mature mast cells which express functional high affinity IgE receptors and contain histamine and tryptase in their granules. In the current study, we further characterize these buffy coat-derived mast cells by studying their responses to common mast cell secretagogues and stabilizers. Mature human mast cells were obtained by culturing isolated progenitors in methylcellulose containing stem cell factor (SCF), IL-3 and IL-6 for 6 weeks and subsequently in liquid medium containing SCF and IL-6 for another 6 to 8 weeks. Following sensitisation with human IgE, these cells released histamine dose-dependently upon activation by anti-IgE and calcium ionophores while compound 48/80 and substance P were relatively ineffective. When the effects of anti-asthmatic agents on anti-IgE-induced mediator release from these cells were compared, only the beta(2)-adrenoceptor agonists and phosphodiesterase inhibitors produced dose-dependent inhibition but not cromolyn or nedocromil. In total, mast cells cultured from human buffy coat progenitors shared similar functional properties of MC(T) subtype of mast cells found predominantly in human lung parenchyma and intestinal mucosa.
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PMID:Histamine release from human buffy coat-derived mast cells. 1732 78

The mechanism of esophageal mucosal injury has gradually been understood at the microbiological level. It is particularly important that pro-inflammatory factors, such as inflammatory cytokines, leukocytes and oxidative stress, have been demonstrated to be involved in the development of gastroesophageal reflux disease (GERD) including nonerosive reflux disease (NERD). Our present study reveals that expression of IL-8 mRNA, a potent neutrophil chemotactic and activating peptide, is correlated with the endoscopic grade of esophagitis or with inflammatory cell infiltration. In addition, it has been shown that bile acids and trypsin can promote IL-8 production from human esophageal epithelial cells via NFkappaB-and AP-1-dependent mechanism. Nociceptors such as acid-sensitive vanilloid receptors, protease-activated receptors and neuropeptides such as substance P have also been implicated in the pathogenesis of neurogenic inflammation in NERD patients with esophageal hypersensitivity. The development of new therapy with antiinflammatory and anti-oxidant effects is expected to assist in the treatment of intractable NERD/GERD and the prevention of carcinogenesis.
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PMID:[Cytokine expression in GERD]. 1751 Dec 18

A large 40-residue precursor peptide (propeptide 5) was synthesized by linking together four designed anticancer peptide analogs to the neuropeptides: vasoactive intestinal peptide, somatostatin, bombesin and substance P, using enzyme cleavable lysyl-lysine linkers. On incubation with the enzyme trypsin, propeptide 5 was cleaved in a sequence-specific manner at the lysyl-lysine residues in the linker to release the individual peptide fragments which were identified by LC-MS. Another precursor peptide (propeptide 5a), consisting of two of the peptide analogs linked through lysyl-lysine linker, was also preferentially cleaved at the Lys-Lys site on incubation with the enzyme trypsin. Propeptide 5 showed potent anticancer activity, both in vitro and in vivo, which was greater than that of the individual component peptides. The enhanced activity suggests that the propeptide is possibly cleaved in the biological system at the lysyl-lysine site to yield the individual peptide analogs, which together show a synergistic effect. On the basis of these experimental findings, it can be concluded that pairs of basic amino acids such as Lys-Lys can be used as facile linkers for delivering multiple biologically active peptides.
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PMID:Delivering multiple anticancer peptides as a single prodrug using lysyl-lysine as a facile linker. 1755 67

Conditions that influence the selective development or recruitment of connective tissue-type and mucosal-type mast cells (MCs) are not well understood. Here, we report that cynomolgus monkey embryonic stem (ES) cells cocultured with the murine aorta-gonad-mesonephros-derived stromal cell line AGM-S1 differentiated into cobblestone (CS)-like cells by day 10-15. When replated onto fresh AGM-S1 with the addition of stem cell factor, interleukin-6, and Flt3 ligand, these CS-like cells displayed robust growth and generated almost 100% tryptase/chymase double-positive MCs within 3 weeks. At all time points, the percentage of tryptase-positive cells did not exceed that of chymase-positive cells. These ES-derived MCs were CD45+/Kit+/CD31+/CD203c+/HLA-DR- and coexpressed a high-affinity IgE receptor on their surface, which was upregulated after IgE exposure. Electron microscopy showed that they contained many electron dense granules. Moreover, ES-derived MCs responded to stimulation by via IgE and substance P by releasing histamine. These results indicate that ES-derived MCs have the phenotype of functionally mature connective tissue-type MCs. The rapid maturation of ES-derived MCs suggests a unique embryonic pathway in primates for early development of connective tissue-type MCs, which may be independent from the developmental pathway of mucosal-type MCs.
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PMID:Direct development of functionally mature tryptase/chymase double-positive connective tissue-type mast cells from primate embryonic stem cells. 1799 16

Chemokines are small proteins (8-12 kD polypeptides) secreted by the cells of innate and adaptive immunity that mediate many of the functions of these cells, including recruitment of other cells. They are classified into families: CC, CXC and CX3C. CXC chemoattract mainly on neutrophils and CC act mainly on monocytes, eosinophils and mast cells. Mast cells are important cells in the modulation of allergic and inflammatory diseases. Activation of mast cells with specific IgE antibody and antigens or other active compounds such as Substance P and corticotrophin releasing hormone causes transcription and translation of several different cytokines/chemokines such as tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1 (MIP-1) and GM-CSF, RANTES, MCP-1, CXCL8, along with other proinflammatory compounds, proteases (chymase and tryptase), histamine, leukotrienes and prostaglandin D2. Neutralization of chemokines may reduce inflammatory cell accumulation and may protect against allergy, toxic shock syndrome and inflammatory diseases.
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PMID:Mast cells and chemokines. 1884 67

There are numerous studies of the pruritus-producing effects of histamine, serotonin, tryptase, substance P and interleukin-2 in humans and mice, but very little reported in dogs even though a common reason dogs are presented to veterinarians is pruritus. The aim of this study was to determine whether substances known to cause pruritus in humans also cause pruritus in dogs. Twenty-five clinically healthy research beagle dogs were included in the study. All dogs first received an intradermal injection of 0.05 mL saline as a control substance and were video-recorded for 20 min before and after the injection. Twenty-four hours later the dogs were randomly divided into five groups of five dogs each and randomly assigned to receive histamine, serotonin, tryptase, substance P or interleukin-2 injected intradermally each at the volume of 0.05 mL. On subsequent days, increasing concentrations of each substance were used. Before (baseline) and after the injection of each concentration of the substances, the dogs were video-recorded for 20 min. The frequency and character of pruritus episodes (scratching, licking, chewing, rubbing or rolling) were noted and these data were used for statistical analysis. The number of pruritus episodes was compared among baseline, saline and the different concentrations of each substance. The results showed that dogs did not have a significant increase in pruritic behaviour above baseline or saline after injection of any of the investigated substances (generalized linear model; P = 0.23).
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PMID:Investigation of the pruritogenic effects of histamine, serotonin, tryptase, substance P and interleukin-2 in healthy dogs. 1915 12

Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED(50) [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value]=0.04 [95% confidence interval 0.01-0.11]mg/paw) and edema (ED(50)=0.08 [95% confidence interval 0.04-0.16]mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin-sensitive afferent fibers as well as pretreatment with the tachykinin NK(1) receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation.
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PMID:Role of TRPV1 in nociception and edema induced by monosodium urate crystals in rats. 2155 Jul 23


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