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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cyclic adenosine 3', 5'-monophosphate (cAMP) content of isolated unstimulated mast cells and the changes induced by a variety of pharmacologic, metabolic, and physical stimuli were studied. A modified bovine serum albumin density gradient purification method consistently provided mast cell preparations which were 95% or more pure, without apparent damage, and a 73% recovery of the mast cells applied to the gradients. The measured cAMP in unstimulated mast cells was high, a mean of 16 picomoles per million cells. Moderate agitation or contact with glass increased cAMP content about 2-fold. When calcium was omitted from the medium mast cell cAMP was markedly elevated; incremental increases in added calcium ion concentration from 1 muM to 1 mM caused a linear decrease in cAMP content. Theophylline (3 to 20 mM) caused a dose-related increase in mast cell cAMP content, approximately 2-fold at 20 mM theophylline. Epinephrine (0.01 to 1 mM) caused a modest, dose-related increase in cAMP. In the presence of theophylline, epinephrine increased cAMP levels equal to or greater than the sum of the effects of the agents used individually. The increase in cAMP induced by epinephrine was completely inhibited by 100 muM propranolol and partially inhibited by 10 muM propranolol, thus suggesting that a beta adrenergic receptor is involved. Prostaglandin E1 (PGE1) and histamine (in the presence of theophylline) also raised cAMP. Carbamylcholine (1 nM) lowered cAMP 38%; Atropine (0.1 mM) inhibited the decrease in cAMP induced by 1 nM carbamylcholine by 83% indicating that a muscarinic receptor is involved. In these homogeneous single cell suspensions, therefore, cholinergic and beta adrenergic agents have opposing effects on cAMP levels. Diazoxide (10 muM) and adenine (1 muM) caused 37 and 32% decreases in cAMP, respectively. The availability of highly purified mast cells and the identification of agents which either decrease or increase cAMP content allows a direct examination of the role of cAMP in histamine release.
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PMID:Modulation of cyclic AMP in purified rat mast cells. I. Responses to pharmacologic, metabolic, and physical stimuli. 4 63

Changes in intracellular and extracellular rat mast cell adenosine 3':5' monophosphate (cAMP) concentrations during stimulation of histamine release by 48/80 were studied. There was a rapid and progressive fall in intracellular cAMP beginning within 10 sec after the addition of 48/80. The lowest cAMP values were obtained at 10 min, with return to control levels by 30 min. The fall in cAMP was dose-related with progressive decreases in 10-min cAMP measurements as the 48/80 concentration was increased from 0.25 to 1.00 mug/ml. There was a graded increase in histamine release over the same concentration range. Attempts to demonstrate significant amounts of cAMP in the medium during 48/80 stimulation were unsuccessful, indicating that the changes in cAMP intracellularly are not due to altered cellular permeability. There was a general correlation between the ability of pharmacologic agents to sustain high intracellular levels of cAMP in the presence of 48/80, and inhibition of histamine release. Theophylline (20 mM) which increased cAMP levels 2- 3-fold prevented a detectable decrease in cAMP after 1 mug/ml 48/80 (measured at 10 min) and almost completely inhibited histamine release. Prostaglandin E1 (27 muM) also raised cAMP levels, decreased the 48/80-induced fall in cAMP (by 42%). Epinephrine increased mast cell cAMP levels, but did not prevent the subsequent 48/80-induced decrease in cAMP and did not inhibit histamine release. Carbamylcholine (1 nM), adenine (1 muM), and diazoxide (10 muM) lowered mast cell cAMP and potentiated 48/80 induced release. In view of previous studies from this laboratory indicating that 48/80 stimulates mast cell phosphodiesterase, it seems likely that the 48/80-induced fall in cAMP is due, at least in part, to increased cAMP destruction. Since agents which prevent the fall in cAMP inhibit histamine release, it is apparent that cAMP is an important part of the control mechanism of histamine secretion. On the other hand, it cannot be concluded that a decrease in cAMP alone is sufficient to produce a response since carbamylcholine, diazoxide, and adenine which lower cAMP do not alter histamine release unless 48/80 is also present.
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PMID:Modulation of cyclic AMP in purified rat mast cells. II. Studies on the relationship between intracellular cyclic AMP concentrations and histamine release. 4 64

Both isobutylmethylxanthine and theophylline increased the level cyclic AMP in the mast cell. Theophylline reduced the allergic histamine release, whereas isobutylmethylxynthine caused a pronounced potentiation of the histamine release. This indicates that the hypothesis of an inverse relationship between the level of cyclic AMP in mast cells and histamine release is too simple.
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PMID:Allergic reactions, cyclic AMP and histamine release. 7 Mar 74

In order to investigate the mechanism of adenosine-induced bronchoconstriction in asthma, serum neutrophil chemotactic activity (NCA) was measured in normal individuals and patients with asthma before and 5 min after bronchoprovocation testing with adenosine. Challenge testing was terminated when the FEV1 fell by 20% or a concentration of 10 mg/ml was reached. Participants were separated into three groups: six asthmatics hyperresponsive to adenosine (Group 1), seven asthmatics hyperresponsive to histamine but not adenosine (Group 2), and six normal subjects (Group 3). The mean percentage increase in NCA was 84% for Group 1 (p less than 0.001), 29% for Group 2 (p less than 0.05), and only 13% for Group 3. No significant increase in NCA was observed after histamine challenge in seven individuals with asthma derived from Groups 1 and 2. Four patients from Group 1 were rechallenged after treatment with therapeutic doses of oral theophylline. Theophylline therapy was associated with a significant attenuation of the increase in NCA at the concentration of adenosine which caused a 20% decrease in FEV1 before treatment (18% versus 84%, p less than 0.01). The concentration of adenosine which caused a 20% drop in FEV1 was increased at least twofold for each of the four patients. Analysis of NCA by gel filtration chromatography demonstrated an increase in a high molecular weight neutrophil chemotactic factor in the serum of two Group 1 patients after adenosine challenge. Release of a high molecular weight neutrophil chemotactic factor is consistent with a mast cell source for inflammatory mediators in adenosine-induced bronchoconstriction. The therapeutic effects of theophylline, a potent adenosine antagonist, in asthma may therefore occur in part through the inhibition of this process.
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PMID:Bronchial challenge with adenosine causes the release of serum neutrophil chemotactic factor in asthma. 202 8

With the use of a collagenase dispersion technique, cells were isolated from the lamina propria of the human small and large intestine. The cell suspensions contained 8% mast cells, which on average contained 1 to 2 pg of histamine/cell. With the use of histochemical procedures based upon fixative sensitivity and dye binding, which identify functionally distinct mast cell subtypes in the rat, dispersed human intestinal mast cells contained approximately equal proportions of two histochemical subtypes analogous to those in the rat. Whether these are functionally distinct as in the rat remains to be determined. The histochemically mixed mast cell populations from the human intestinal mucosa secreted histamine in a dose- and energy-dependent manner in response to anti-IgE and A23187, but not 48/80. Theophylline, doxantrazole, quercetin, and salbutamol all significantly inhibited anti-IgE-induced histamine secretion by human intestinal mast cells, but cromolyn sodium and the experimental antisecretory drugs, nedocromil sodium and FPL 52694, did not inhibit histamine secretion by the mast cell mixture to a statistically significant extent. Cromolyn sodium inhibited histamine secretion by 15 to 30%, and whether this reflected inhibition of one of the two histochemical mast cell subtypes to a greater extent than the other or all the cells to a minimal degree remains to be established. Control investigations of the intestinal cell isolation procedure indicated that these qualities did not reflect effects of the cell dispersal procedure. Further characterization and analysis of intestinal mast cells is essential to determine if functionally distinct mast cell subtypes exist in human tissues.
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PMID:Mast cells from the human intestinal lamina propria. Isolation, histochemical subtypes, and functional characterization. 243 1

Human synovium obtained at arthroplasty from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) were characterized by assessing mast cell morphology, content and function. Histological studies confirmed significant numbers of mast cells in both RA and OA synovium. Electron microscopic data support the morphologic similarity between human synovial mast cells and human mast cells in lung and intestine. Likewise, synovial mast cells do not appear to be functionally different from pulmonary or intestinal mucosal mast cells. Mast cell suspensions with a cellular histamine content of 4.3 +/- 0.5 pg/cell (mean +/- SEM) released histamine following provocation with anti-IgE and calcium ionophore but not compound 48/80, f-met peptide or bradykinin. Prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) were also released in response to anti-IgE. Auranofin inhibited anti-IgE provoked histamine, PGD2 and LTC4 release while gold sodium thiomalate, cromolyn and indomethacin had no effect on histamine release. Theophylline inhibited anti-IgE induced histamine release only at concentrations greater than or equal to 10(-3) M. Our study argues against functional or morphologic mast cell heterogeneity of human intestinal, lung and synovial origin and suggests that mast cells may have a pathogenic role in both RA and OA.
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PMID:Characterization of human synovial mast cells. 246 48

Theophylline and enprofylline have been demonstrated to reduce mast cell-mediator release, inhibit polymorphonuclear leukocyte activation, and have been reported to reduce the late bronchial response to antigen. The effects of theophylline and enprofylline on the late cutaneous response (LCR) to compound 48/80 and antigen were studied in 29 patients enrolled in a placebo-controlled, double-blind study of the effect of the xanthines in mild asthma. Skin testing to a common environment allergen and compound 48/80 was performed during a baseline period and in the second phase of the study after stable drug levels were achieved, at least 6 weeks later. During baseline, the mean immediate wheal diameter (IWD) with antigen was 15.7 mm +/- 0.5, resulting in 27/29 LCRs with a mean wheal diameter of 37.1 mm +/- 5.2. The mean IWD with compound 48/80 was 16.1 mm +/- 0.7, resulting in 26/29 LCRs with a mean wheal diameter of 19.6 mm +/- 2.8. Repeat skin testing during treatment revealed no statistically significant changes in the LCR elicited by antigen or 48/80 in any of the treatment groups. There was little correlation between the size of the immediate wheal produced by antigen or 48/80 and the resulting size of the late response (r = 0.174 to 0.519). However, for the same IWD, the resulting late response was smaller with 48/80 than with antigen (p = 0.003). We conclude that (1) theophylline and enprofylline have no effect on the LCR to 48/80 and antigen and (2) for equivalent immediate wheal sizes, the resulting late response is smaller with 48/80 than with antigen.
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PMID:The effect of theophylline and enprofylline on the late cutaneous response to antigen and compound 48/80. 291 85

Aminophylline-treated mouse bone marrow-derived mast cells exhibit a hyperresponsiveness to adenosine addition (10(-6) to 10(-4) mol/L) at the time of secretagogue challenge coincident with an up regulation of adenosine receptor numbers. This effect on beta-hexosaminidase release is maximal at 100 mumol/L of aminophylline, evident after 5 days of aminophylline exposure, and reversed by 6 days after washing. Neither radiolabeled arachidonic acid nor leukotriene C4 release in the absence or presence of adenosine was altered by aminophylline treatment. Although cAMP levels were dynamically changed by adenosine or secretagogue, these changes were not different in the two cell populations; resting and challenged mast cell adenosine levels were similarly unaffected by aminophylline. The long-term action of aminophylline on mouse bone marrow-derived mast cells appears to be primarily on adenosine receptors and thereby on preformed mediators, and this action may have some importance in the pathophysiology and treatment of asthma.
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PMID:Aminophylline exposure alters mouse bone marrow-derived mast cell adenosine responsiveness. 302 Jan 10

Activation of white cells, including the neutrophil, eosinophil, basophil, and mast cell, has long been known to be suppressed by high, nonphysiological levels of E-prostaglandins (PGE). In contrast, PGE at levels consistent with an interaction with the PGE receptor (5 X 10(-9) M) have recently been shown to suppress leukotriene (LT) and prostaglandin (PG) production by neutrophils and eosinophils. This occurs by cyclic AMP-dependent inhibition of release of substrate arachidonic acid (AA) from phospholipid pools. The additional observation that indomethacin (10(-9) M) enhances release of eicosanoids by suppressing endogenous PGE2 acting to increase cAMP levels in these cells. Theophylline and other phosphodiesterase inhibitors precisely duplicate the action of PGE2, and the combined effects of such phosphodiesterase inhibitors and adenylate cyclase stimulators are synergistic. The mechanism of action of theophylline in asthma is not know, although it is generally agreed that its effect is a direct one on the bronchial smooth muscle. The findings described in this report now permit the bronchial smooth muscle, but is primarily one of suppressing mediator release from relevant white cells by inhibition of cAMP phosphodiesterase, an action that is enhanced by the presence of inflammatory prostaglandins in the lung.
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PMID:Cyclic AMP-dependent regulation of lipid mediators in white cells. A unifying concept for explaining the efficacy of theophylline in asthma. 303 56

Platelet-activating factor (PAF) has recently been shown to be a potent ulcerogenic agent in the stomach and intestinal mucosa. Its extract mechanism of action is not yet known although histological studies suggest that vasocongestion is an important feature of PAF-induced damage. We have therefore studied the activity of various agents with different modes of action toward PAF-induced gastrointestinal lesions in the rat (PAF 2 micrograms/kg i.v.; macroscopic lesions of tissue scored 20 min later; arbitrary scale from 0 to 4). Drugs were administered either i.m., s.c. (5 min) or orally (30 min) before PAF injection. PAF-induced gastric lesions were strongly inhibited by the natural PAF-antagonist BN 52021 as well as by atropine sulphate and cimetidine which implicates cholinergic stimulation in the ulcerogenic activity of PAF. The somatostatin analog BIM 23014 was also very potent against PAF, perhaps by reducing the parasympathetic stimulation in the gastric wall as described for somatostatin. Allopurinol, which is a free radical scavenger also almost totally inhibited PAF-induced gastric damage, suggesting that neutrophils are involved in the mucosal lesions. The considerable inhibition of the gastric effects of PAF found in neutrophil-depleted animal supports this hypothesis. Theophylline and disodium cromoglycate, mast cell stabilizing drugs which were also active in our model, could act by protecting mast cell degranulation induced by free radicals released from activated neutrophils. A multifunctional process seems to determine the mucosal gastric damage induced by PAF, but parasympathetic stimulation and neutrophil activation play a major role in this pathology.
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PMID:Role of neutrophils in gastric damage induced by platelet activating factor. 324 84


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