Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence suggests that nonadrenergic airway relaxation may be controlled by vasoactive intestinal peptide (VIP). The magnitude and duration of smooth muscle relaxation in response to VIP may be influenced by rates of peptide degradation after release from efferent peptidergic neurons. To explore the potential role of mast cell mediators in modulating neural control of airway tone, we studied the effect of the mast cell proteases tryptase and chymase on airway smooth muscle relaxation induced by VIP in ferret airway. Tracheal rings precontracted by serotonin (10(-6) M) in a muscle bath were relaxed by VIP (10(-7) M). We found that protease-rich supernatant obtained by degranulation of dog mastocytoma cells reversed VIP-induced relaxation, as did highly purified tryptase and chymase incubated with the tracheal rings. Either enzyme completely reversed the effect of VIP, but tryptase was more potent than chymase, paralleling previous test tube observations on the relative rates of VIP cleavage by the two enzymes. Inhibitors of mast cell tryptase and chymase preincubated with the supernatant or with the purified proteases prevented reversal of VIP-induced relaxation. Mast cell proteases did not reverse the tracheal relaxation caused by the nonpeptide adrenergic agonist isoproterenol. These findings show that mast cell proteases tryptase and chymase counteract the smooth muscle relaxant effects of VIP in ferret trachea and suggest a potential role for the mast cell proteases in the modulation of nonadrenergic neural control of airway tone by VIP.
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PMID:Mast cell tryptase and chymase reverse airway smooth muscle relaxation induced by vasoactive intestinal peptide in the ferret. 249 55

The purpose of this study was to determine if asbestos-induced pulmonary fibrosis in the rat can affect the levels of autacoids and peptides in freshly isolated lung cells. Lung fibrosis was experimentally induced in rats by a single intratracheal instillation of 5 mg UICC Canadian chrysotile B fibers. Isolated lung cells were prepared from normal and from asbestos-exposed rats. These cells were also fractionated on bovine serum albumin (BSA) gradients. The contents of serotonin (5-HT), histamine (HIST), vasoactive intestinal peptide (VIP), and bombesin (BN) were measured in isolated total cell preparations as well as in density-fractionated cell populations from normal and from asbestos-exposed rats. Analysis of total lung cell preparation showed the presence of heterogeneous populations in normal rat lung. After asbestos exposure, there were significant changes in these cell populations as evidenced by significant increases in lymphocyte and mast cell numbers. In addition, increased levels of 5-HT, HIST, and VIP were observed in isolated lung cells obtained from rats exposed to asbestos 1, 3, and 6 months after instillation. BN content was unchanged 3 months after treatment, but was significantly increased at the 6 month-interval, suggesting a different pattern of response for this neuropeptide. Density fractionation of various cell populations further showed selective changes in specific cell fractions of lung after asbestos exposure. At 6 months, increased levels of 5-HT, HIST, and VIP were associated with cell fraction 7, whereas changes in BN content were found in cell fractions 2 and 3. Similarly, there was a significant increase of mast cells in fraction 7 at the 6-month interval.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in autacoid and neuropeptide contents of lung cells in asbestos-induced pulmonary fibrosis. 288 13

In addition to cholinergic neural mechanisms, airway tone is influenced by adrenergic mechanisms and by more recently described neural mechanisms which are non-adrenergic and non-cholinergic (NANC). Sympathetic innervation to human airways is very sparse and there is no functional adrenergic innervation of smooth muscle, although sympathetic fibres may supply ganglia, submucosal glands and bronchial vessels. Airway tone may be influenced by circulating adrenaline and there is some evidence that adrenaline secretion may be impaired in asthma. beta-Adrenoceptors (which are almost entirely of the beta 2-subtype) are localized to many cell types in airways and beta-agonist may be beneficial in airway obstruction, not only by directly relaxing airway smooth muscle (from trachea to terminal bronchioles), but by inhibiting mast cell mediator release, by modulating cholinergic nerves, by reducing bronchial oedema and by reversing the defect in mucociliary clearance. There is little evidence that beta-receptor function is impaired in asthma. Alpha-adrenoceptors, which are bronchoconstrictor, may be activated by inflammatory mediators and disease, and alpha-agonists cause bronchoconstriction in asthmatic patients. However, alpha-antagonists have little effect, which questions the role of alpha-receptors in asthma. NANC nerves which relax human airways have been demonstrated in vitro. Although the neurotransmitter is not certain, there is now convincing evidence that it may be vasoactive intestinal peptide (VIP) and a related peptide histidine methionine (PHM). VIP and PHM immuno-active nerves are found in human airways, and both peptides potently relay human airways in vitro (but not in vivo because of diffusion and metabolism problems).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adrenergic and non-adrenergic, non-cholinergic control of airways. 303 86

We have tested the effects of intravenous injections of substance P (SP), bradykinin (BK), somatostatin (SS) and vasoactive intestinal peptide (VIP) on the blood pressure, histaminemia and hematocrit in pentobarbital-anesthetized rats. The four peptides elicited a decrease of the mean arterial blood pressure which varied both in amplitude and in duration depending both on the peptide and on the doses utilized. The hypotensive effects of SP and VIP were more persistent than those caused by BK or SS. Only SP evoked an increase of histaminemia. Both SP and BK caused an increase of hematocrit. The change of hematocrit was more prominent and of longer duration after Sp than after BK. Pretreatment of rats with the antiinflammatory drug dexamethasone inhibited markedly the changes of blood pressure, histaminemia and hematocrit caused by SP. The hypotensive effects of BK, SS and VIP as well as the transient change of hematocrit evoked by BK were not affected by dexamethasone. The results suggest that part of the hypotensive activity and changes of hematocrit evoked by SP in rats is due to the release and action of histamine and possibly of other vasoactive substances, of mast cell origin. The results also indicate that mast cell mediators, particularly histamine, are unlikely to be instrumental in the hypotensive activity of BK, SS or VIP in rats.
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PMID:Evaluation of the contribution of mast cell mediators to the hypotensive activity of various peptides in rats. 619 Dec 39

The common pathway of heterogenous mast cell activation as mediated by antigens is through the cross-linking of IgE bound to Fc epsilon RI receptors. The peptidergic pathway of mast cell activation, achieved by cationic secretagogues, is restricted to "serosal" mast cells, the experimental models being rat peritoneal and human skin mast cells. Cationic secretagogues include positively charged peptides but also various amines such as compound 48/80 and natural polyamines. An early intracellular event of this pathway is the activation of pertussis toxin-sensitive G proteins. The correlation observed between the ability of basic compounds to trigger mast cell exocytosis and their potency to activate purified G proteins strongly suggests that cationic compounds activate mast cell G proteins via a receptor-independent but membrane-assisted process. In this paper, alternative mechanisms are discussed. The consequence of G protein stimulation is the activation of phospholipase C with an increase in inositol triphosphates. Natural polyamines are relatively poor triggers of mast cells (10(-4) to 10(-2) M). Neuropeptides such as substance P, neuropeptide Y or vasoactive intestinal peptide, peptidic hormones such as kinins, and venoms such as mastoparan and mast cell degranulating peptide, are all active in a concentration range from 10(-7) to 10(-4) M. The cationic anaphylatoxin C3a also stimulates mast cells at concentrations below precursor complement C3 blood levels. The component C3 of the complement system is one of only a few plasma proteins having activation fragments (i.e. C3a) that can be generated at micromolar levels. The effects of basic secretagogues defines a peptidergic pathway of mast cell activation, which represents a potentially toxic process considering the tissue effects caused by exogenous basic compounds such as venom peptides and certain amine containing drugs. Peptidergic activation of mast cells may also be a pathophysiological process having an important role in neurogenic inflammation and in diseases involving extensive activation of the blood complement cascade.
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PMID:Peptidergic pathway in human skin and rat peritoneal mast cell activation. 751 63

To elucidate the possible role of vasoactive intestinal peptide (VIP) in the pathogenesis of acute gastric mucosal damage, rats were treated intragastrically with 1.0 ml 96% ethanol with or without intravenous or intraperitoneal coadministration of VIP (1 nmol/liter to 1 mumol/liter/100 g). VIP was found to double the mean lesion area when compared with that induced by ethanol alone (P < 0.05), an effect that was prevented by VIP antagonist (1 mumol/liter/100 g). A substance P antagonist (1 mumol/liter/100 g) also reduced the extent of gastric damage induced by coadministration of VIP and ethanol. VIP antagonist or substance P antagonist significantly reduced ethanol-induced gastric mucosal damage. Gastric mucosal levels of LTB4, LTC4, VIP, and substance P were significantly increased in ethanol-treated rats as compared with saline-treated animals (P < 0.05). The augmentation of ethanol-induced damage by VIP was associated with increased gastric mucosal levels of LTB4. In VIP-treated rats, gastric mucosal levels of substance P were found to be significantly increased compared with control rats (P < 0.05). Administration of VIP to pyloric-ligated rats significantly increased gastric acid output and blood pepsinogen A levels as compared with saline treated rats (P < 0.05). Ketotifen, a mast cell stabilizer (100 micrograms/100 g), administered orally 30 min before damage induction by ethanol, with or without VIP, totally abolished the damage of the surface epithelium of the entire gastric mucosa and significantly reduced the mucosal levels of LTC4 and LTB4 (P < 0.05). It is suggested that VIP is involved in the pathogenesis of acute ethanol-induced gastric mucosal damage.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of vasoactive intestinal peptide (VIP) in pathogenesis of ethanol-induced gastric mucosal damage in rats. 768 41

Tryptases are trypsin-like enzymes found in mast cell granules that appear to exist as tetramers. These enzymes are not controlled by blood plasma proteinase inhibitors and only cleave a few physiological substrates in vitro, including high-molecular-mass kininogen (HMMK) and vasoactive intestinal peptide (VIP). Purified human lung mast cell tryptase (HLT) contained two bands of approx. molecular mass 29 and 33 kDa on SDS/PAGE. These two forms of HLT have been separated by chromatography on a cellulose phosphate column, with the high-molecular-mass form (high-HLT) being eluted with 10 microM heparin and the low-molecular-mass form (low-HLT) subsequently eluted with 1 M NaCl. Removal of asparagine-linked carbohydrate caused both isoforms to run as single sharp bands on SDS/PAGE, differing slightly in molecular mass. Separation of these two isoforms of tryptase shows that tetramers consist of four homologous subunits rather than mixtures of the two isoforms. Using HMMK and VIP as substrates, these two forms of HLT were found to differ with regard to specificity and rate of cleavage. High-HLT initially cleaved HMMK at Arg-431 within the C-terminal anionic binding region of the molecule, whereas low-HLT cleaved HMMK simultaneously at multiple sites within the C-terminal portion of the molecule. On the basis of HPLC peptide mapping, each isoform also cleaved VIP at different sites. Comparison of cleavage rates based on the active-site concentrations of titrated isoforms showed that low-HLT cleaved HMMK more rapidly than did high-HLT. These two isoforms may represent different gene products or they may result from post-translational modification.
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PMID:Human mast cell tryptase isoforms: separation and examination of substrate-specificity differences. 773 67

The existence of a protein approximately 48% identical with mast cell tryptases was predicted previously from a dog mastocytoma cDNA. Antibodies raised against a peptide based on the deduced sequence suggested that the protein (dog mast cell protease-3, dMCP-3) is expressed in mast cells. In this report, characterization of the protein purified from mastocytomas reveals an N-glycosylated, high molecular weight, tryptic serine protease, which appears to be a tetramer of catalytic subunits, approximately half of which are linked by disulfide bonds. The oligomeric complex yields a single NH2-terminal sequence, which is identical with that predicted by dMCP-3 cDNA. This finding, and the lack of closely related genes on blots of genomic DNA, predict that each subunit is the product of one gene. Although dMCP-3 binds to heparin, it is active and stable at low ionic strength in heparin's absence. It resists inactivation by inhibitors in plasma but is sensitive to small inhibitors, e.g. leupeptin and bis(5-amidino-2-benzimidazolyl)methane (BABIM). dMCP-3 hydrolyzes extended peptidyl p-nitroanilides ending in basic residues, with P1 arginine preferred to lysine; it hydrolyzes the Arg18-Ser19 bond of calcitonin gene-related peptide but cleaves neither vasoactive intestinal peptide nor casein. These data suggest that dMCP-3 is a unique serine protease whose stability, formation of intersubunit disulfide bonds, inhibitor susceptibilities and substrate preferences differ from those of its closest relatives, the mast cell tryptases.
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PMID:Purification and characterization of dog mast cell protease-3, an oligomeric relative of tryptases. 776 12

Tryptase and chymase released from activated mast cells degrade the neuropeptides calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) to peptide fragments. We have examined whether nedocromil sodium can modulate the ability of rat activated peritoneal mast cells to degrade 125I-CGRP and 125I-VIP. Mast cell-dependent degradation of both 125I-CGRP and 125I-VIP was observed with compound 48/80 (0.03-1 microgram/ml) and in the case of 125I-VIP with anti-IgE (1-20 micrograms/ml). Nedocromil sodium (10(-6)-10(-4) M) caused significant inhibition of neuropeptide degradation, with the most effective inhibition observed against anti-IgE-induced degradation of 125I-VIP. Nedocromil sodium had no inhibitory effect on the ability of lysed mast cells, bovine trypsin or chymotrypsin to breakdown 125I-VIP. These results suggest that nedocromil sodium inhibits mast cell-dependent degradation of neuropeptides, such as VIP, as a secondary consequence of inhibiting the release of mast cell proteases.
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PMID:The modulation by nedocromil sodium of proteases released from rat peritoneal mast cells capable of degrading vasoactive intestinal peptide and calcitonin gene-related peptide. 839 43

Radioimmunoassays for neuroendocrine vasoactive intestinal peptide (VIP1-28) detected 30-120 fmol of structurally related peptides in extracts of 10(7) mouse peritoneal mast cells, bone marrow-derived mast cells, cultured PT-18 and C1.MC/C57.1 lines of mast cells, and rat basophilic leukemia (RBL) cells. No VIP was found in peritoneal cells of mast cell-deficient WBB6F1-W/Wv mice, whereas the amounts extracted from peritoneal cells of the congenic normal (WBB6F1-+/+) mice were similar to those from cultured mouse mast cells. Sephadex G-25 gel filtration resolved two different-sized variants of VIP from mouse mast cells and RBL cells. Amino acid sequence analyses showed that the smaller variant is VIP10-28. The principal amino-terminally larger variant of VIP from C1.MC/C57.1 mouse mast cells and RBL cells exhibited amino acid sequence homology with VIP(-6)-28, and this sequence was established for the corresponding larger VIP from PT-18 mast cells. Polymerase chain reaction amplification of two different substituent sequences of prepro VIP in RBL cell RNA identified the VIP message. VIP10-28 was released from mouse mast cells concurrently with histamine by IgE-dependent stimulation. Rodent mast cell-derived VIP thus consists of both the truncated VIP10-28 and amino-terminally larger forms that appear to be generated by peptidolysis of a preproVIP similar to that found in neural cells.
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PMID:Variants of vasoactive intestinal peptide in mouse mast cells and rat basophilic leukemia cells. 840 43


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