The clinical relevance of basophil releasability.
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Aging↗
Biomedical subjects
G Marone
Publications and source records attributed to G Marone.
Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor.
Platelet-activating factor (PAF) can exert profound inflammatory effects at very low concentrations. In plasma, PAF is hydrolyzed to lyso-PAF by acetylhydrolase, an enzyme that circulates bound to LDL. Previous studies suggest that oxygen radicals may act synergistically with PAF to potentiate tissue injury. However, mechanisms underlying this interaction have not been elucidated. In this study we investigated whether oxygen radicals may inactivate PAF acetylhydrolase. PAF acetylhydrolase activity was measured in human plasma and purified LDL before and after exposure to radicals (10-20 nmol/min per ml) generated by xanthine/xanthine oxidase. Oxygen radicals induced > 50% loss of PAF acetylhydrolase activity within 60 s and almost complete inactivation by 10 min. This phenomenon was irreversible and independent of oxidative modification of LDL. Inactivation occurred without changes in the affinity constant of the enzyme (Km was 17.9 microM under control conditions and 15.1 microM after exposure to oxygen radicals). Inactivation was prevented by the scavengers superoxide dismutase or dimethylthiourea or by the iron chelator deferoxamine. Thus, superoxide-mediated, iron-catalyzed formation of hydroxyl radicals can rapidly and irreversibly inactivate PAF acetylhydrolase. Since concomitant production of PAF and oxygen radicals can occur in various forms of tissue injury, inactivation of acetylhydrolase might represent one mechanism by which oxygen radicals may potentiate and prolong the proinflammatory effects of PAF.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
In vivo characterization of the anti-inflammatory effect of cyclosporin A on human basophils.
We investigated whether cyclosporin A (CsA) in vivo exerts anti-inflammatory effects by inhibiting IgE- and non-IgE-dependent mediator release from human basophils. Six healthy volunteers were given oral CsA (5 mg/kg twice daily) or placebo for 5 days. Plasma CsA and basophil releasability in response to anti-IgE, FMLP, and A23187 were monitored 1 day before treatment, on alternate days during the treatment course, and 1 and 8 days after cessation of treatment. A constant plasma level of approximately 250 ng/ml CsA was obtained during CsA treatment. Basophil releasability in response to anti-IgE, FMLP, and A23187 was diminished by 20 to 60% throughout the course of CsA treatment. Placebo had no effect on basophil releasability. There was a significant correlation between plasma CsA and the decrease of histamine release induced by anti-IgE (rs = -0.66; p < 0.0005), FMLP (rs = -0.59; p < 0.001) and A23187 (rs = -0.68; p < 0.0001). In a second study, eight normal volunteers were given a single oral dose of CsA (7 mg/kg) or placebo, and plasma CsA and basophil releasability were monitored at different times thereafter. A rapid and significant reduction of histamine release induced by anti-IgE, FMLP, and A23187 paralleled a sharp increase of CsA plasma levels, which peaked at 5 h and lasted approximately 13 h. This study indicates that oral administration of CsA in normal subjects causes a rapid and significant inhibition of histamine release from basophils. This is the first evidence that in vivo administration of CsA can modulate the release of proinflammatory mediators from basophils obtained ex vivo.
Adolescent↗
Protein Fv produced during vital hepatitis is a novel activator of human basophils and mast cells.
Protein Fv is found in the normal liver and is released in the stools of patients suffering from viral hepatitis. Protein Fv isolated from five patients stimulated the release of histamine and sulfidopeptide leukotriene C4 from purified and unpurified peripheral blood basophils. Protein Fv absorbed with protein A-Sepharose coated with polyclonal IgG did not induce histamine secretion, whereas removal of putative contaminating Ig did not modify the releasing activity. The characteristics of the release reaction were similar to those of rabbit IgG anti-Fc fragment of human IgE (anti-IgE). There was an excellent correlation (Spearman rank coefficient (rs) = 0.83; p < 0.001) between the maximal percent histamine release induced by protein Fv and that induced by anti-IgE from basophils. Preincubation of basophils with either protein Fv or anti-IgE resulted in complete cross-desensitization to a subsequent challenge with heterologous stimulus. Basophils from which IgE had been dissociated by brief exposure to lactic acid no longer released histamine in response to anti-IgE and protein Fv. A monoclonal IgE purified from a myeloma patient (patient ADZ) blocked both anti-IgE- and protein Fv-induced releases, whereas human polyclonal IgG and a monoclonal IgG purified from another myeloma patient (patient ZEG) selectively blocked protein Fv-induced secretion. Protein Fv also induced the release of preformed (histamine and tryptase) and de novo synthesized mediators (sulfidopeptide leukotriene C4 and/or PGD2) from mast cells purified from human lung parenchyma and skin tissues. There was a significant correlation between the maximal percent histamine release induced by protein Fv and anti-IgE from skin mast cells (rs = 0.63; p < 0.01). There was also an excellent correlation between histamine and tryptase release caused by protein Fv from both lung (rs = 0.80; p < 0.001) and skin mast cells (rs = 0.70; p < 0.01). Thus, we established that protein Fv acts as a novel activator of human basophils and mast cells presumably by interacting with the VH domain of the IgE.
Animals↗
Anti-inflammatory effects of glucocorticoids and cyclosporin A on human basophils.
Pro-inflammatory and vasoactive mediators released from human basophils and mast cells play a role in several inflammatory and immune disorders. It was recently demonstrated that cyclosporin A (CsA) exerts anti-inflammatory effects by inhibiting the release of preformed and de novo synthesized mediators from human basophils. This study compared the effects of pharmacological concentrations of deflazacort (DFZ) and prednisolone (PRED) on the anti-IgE-mediated release of preformed (histamine) and de novo synthesized (leukotriene C4: [LTC4]) mediators from basophils. Basophils were cultured for 18 hours in the presence of pharmacological concentrations of DFZ (10(-8) to 3 x 10(-6) M). DFZ inhibited the anti-IgE-mediated release of histamine and LTC4 from basophils in a concentration-dependent manner (6-40%), and had a similar efficacy and potency to PRED. The effect of DFZ (10(-8) to 10(-7) M) in combination with CsA on the immunological release of histamine and LTC4 from basophils was also evaluated. An 18-hour incubation of basophils with DFZ (10(-8) M) followed by a short (15-minute) incubation with CsA (30 ng/ml) resulted in an additive inhibition of the release of histamine and LTC4. The additive anti-inflammatory effect of these drugs makes them interesting candidates for future controlled clinical trials in inflammatory diseases in which basophil-derived mediators play a relevant role.
Anti-Inflammatory Agents↗
Mechanisms of activation of human mast cells and basophils by general anesthetic drugs.
A study was performed about the effects of increasing concentrations of muscle relaxants (suxamethonium, d-tubocurarine, vecuronium, and atracurium), hypnotics (propofol, ketamine, and thiopental), opioids (morphine, buprenorphine, and fentanyl), and benzodiazepines (diazepam, flunitrazepam, and midazolam) on the release of preformed (histamine and tryptase) and de novo synthesized (prostaglandin D2: PGD2 and peptide-leukotriene C4: LTC4) chemical mediators from human basophils and mast cells isolated from skin (HSMC), lung parenchyma (HLMC) and heart tissue (HHMC). None of the drugs tested induced the release of histamine or LTC4 from basophils of normal donors. Suxamethonium did not induce mediator release from any type of human mast cell tested. Only the highest concentration of d-tubocurarine used caused histamine release from HSMC and HLMC. Atracurium, more than vecuronium, induced concentration-dependent histamine release from HSMC and HLMC. Propofol induced a concentration-dependent histamine release from HLMC, but not from HHMC. Only the highest concentrations of ketamine and thiopental used caused a significant release of histamine from HLMC. The muscle relaxants and hypnotics examined did not induce any de novo synthesis of PGD2 or LTC4 in mast cells. Morphine only induced histamine and tryptase release from HSMC, but not the de novo synthesis of PGD2. In contrast, buprenorphine caused histamine and tryptase release from HLMC, and not from HSMC, whilst it also induced de novo synthesis of PGD2 and LTC4 in HLMC. Fentanyl did not give any histamine and tryptase release from mast cells. Diazepam and flunitrazepam only induced a small release of histamine from mast cells, whereas midazolam caused the release of histamine from HLMC. The biochemical pathways underlying the release of mediators from human mast cells induced by drugs used during general anaesthesia are different from those underlying the immune release of histamine. From the results obtained with the in vitro model described here, it is clear that new drugs promising for the anesthesiologic arena should be tested in vitro before their potential histamine-releasing activity is experienced in vivo.
Analgesics, Opioid↗
Livedo reticularis in a patient with systemic lupus erythematosus and anticardiolipin antibodies.
This report describes a case of livedo reticularis associated with increased titres of anticardiolipin antibodies (aCL) in a patient with systemic lupus erythematosus. A 38-year-old woman presented with fever, malaise, arthritis and livedo reticularis in a severe form. Antibodies to native DNA and an increased level of aCL were found. A significant positive correlation exists between livedo reticularis and elevated serum antiphospholipid activity in patients with systemic lupus erythematosus. aCL are shown to play a possible pathogenetic role in thrombotic events. This suggests that thrombosis is the underlying cause of livedo in these patients. A biopsy performed in a patient at the site where livedo was most marked showed no evidence of thrombi. It is postulated that the mechanism of livedo in lupus patients with aCL consists of both thrombosis and dysfunction in the regulation of the tone of the peripheral vascular bed.
Adult↗
Cardiac involvement in rheumatoid arthritis: an echocardiographic study.
Thirty-nine consecutive patients with rheumatoid arthritis (RA) and 40 control subjects were studied by echocardiography in order to assess the incidence of cardiac involvement in this disease. The occurrence of anatomic lesions in our series was lower than that observed in other studies. No differences in mean values of left and right ventricular diastolic function indexes obtained by Doppler echocardiography were found between patients and controls. However, in 26% of patients with RA, left ventricular abnormalities probably secondary to myocardial fibrosis were observed.
Arthritis, Rheumatoid↗
Nimesulide, a sulfonanilide nonsteroidal anti-inflammatory drug, inhibits mediator release from human basophils and mast cells.
Nimesulide (NIM) is a sulfonanilide nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of various inflammatory diseases and chemically unrelated to other acidic NSAIDs, such as acetylsalicylic acid (ASA) and indomethacin (INDO). We investigated the effects of NIM and of its in vivo metabolite, 4-hydroxy-NIM (OH-NIM), on the release of performed (histamine) and de novo synthesized mediators (sulfidopeptide leukotriene C4 [LTC4] and prostaglandin D2 [PGD2]) from human basophils and mast cells isolated from lung parenchyma (HLMC) and skin (HSMC). Histamine release from basophils challenged with rabbit anti-human IgE antibody (anti-IgE) was enhanced by preincubation with ASA or INDO (92.2 +/- 7.1% at 10(-3) M and 61.1 +/- 6.7% at 3 x 10(-6) M, respectively; P < .001). In contrast, NIM and its metabolite, OH-NIM (10(-6) to 10(-3) M), caused concentration-dependent inhibition (2.9 to approximately 60% and 3.7 to approximately 90%, respectively) of IgE-mediated histamine release from basophils. NIM and OH-NIM also inhibited histamine release from basophils induced by the Ca++ ionophore A23187 and different protein kinase C activators, such as 12-O-tetradecanoyl-phorbol-13-acetate, bryostatin 1 and bryostatin 5. NIM and OH-NIM also inhibited the IgE-mediated histamine release from HLMC (52.3 +/- 9.6% and 66.1 +/- 12.1% at 10(-3) M, respectively; P < .0001) and HSMC (67.3 +/- 3.7% and 77.7 +/- 12.0% at 10(-3) M, respectively; P < .0001) but had little or no effect on HLMC and HSMC activated by A23187. NIM (10(-6) to 10(-3) M) markedly inhibited the de novo synthesis of LTC4 from basophils, LTC4 and PGD2 from HLMC and PGD2 from HSMC. NIM and OH-NIM potentiated, whereas ASA and INDO reversed, the inhibitory effect of adenylate cyclase agonists, such as prostaglandin E1 and forskolin. In addition, NIM and OH-NIM reversed the enhancing effects of ASA and INDO on IgE-mediated histamine release from basophils.
Adolescent↗
A comparison of fluticasone propionate, 1 mg daily, with beclomethasone dipropionate, 2 mg daily, in the treatment of severe asthma. International Study Group.
We wanted to compare the efficacy and safety of fluticasone propionate, a new topically active inhaled corticosteroid, to that of high dose beclomethasone dipropionate, in severe adult asthma. Patients currently receiving between 1.5-2.0 mg.day-1 of an inhaled corticosteroid were treated for six weeks in a double-blind, randomized, parallel group study with 1 mg.day-1 fluticasone propionate (n = 82), or 2 mg.day-1 beclomethasone dipropionate (n = 72). Mean morning peak expiratory flow rates (PEFR) increased from 303 to 321 l.min-1 with fluticasone propionate, and from 294 to 319 l.min-1 with beclomethasone dipropionate. There was an increase in evening PEFR, asthma symptoms improved, and rescue beta 2-agonist use decreased for both treatment groups. None of these differences between treatments were statistically significant. However, diurnal variation was significantly reduced with fluticasone propionate, when compared with beclomethasone dipropionate (difference = 7 l.min-1; p = 0.038). Clinic lung function also improved with both treatments and, apart from % predicted PEFR, which showed no difference after beclomethasone dipropionate but increased from 73 to 78% with fluticasone propionate, there were no differences between treatments. Forced expiratory volume in one second (FEV1) increased with both treatments. The geometric mean plasma cortisol concentration rose after treatment with fluticasone propionate (from 293 to 309 nmol.l-1) and fell after beclomethasone dipropionate (from 256 to 224 nmol.l-1); the difference between treatments was significant. The incidence of adverse events was low in both treatment groups. In conclusion, 1 mg.day-1 fluticasone propionate was as effective as 2 mg.day-1 beclomethasone dipropionate in the control of severe asthma.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Topical↗
Heterogeneity of human Fc epsilon RI-bearing cells.
Basophils and mast cells (Fc epsilon RI-bearing cells) play important but clearly distinct roles in human inflammatory and allergic reactions. While many similarities have been described, it is increasingly evident that many more differences exist between these two cell types. These include maturational and ultrastructural as well as functional differences. Basophils and mast cells can be activated by different stimuli, produce different profiles of inflammatory mediators, and their response can be modulated in a different fashion. The heterogeneity of Fc epsilon RI-bearing cells has recently been extended by studies on mast cells isolated from different human tissues. These studies may suggest the existence of different human mast cell phenotypes the development of which may be regulated by microenvironmental factors. A better understanding of the heterogeneity of basophils and mast cells is a necessary step to define their respective roles in the pathophysiology of human inflammatory responses.
Basophils↗
Spectrum of cardiac involvement in systemic lupus erythematosus: echocardiographic, echo-Doppler observations and immunological investigation.
Cardiac involvement was noninvasively evaluated in 75 consecutive patients with systemic lupus erythematosus (SLE) by two-dimensional and Doppler echocardiography. In 50/75 patients anticardiolipin antibodies (aCL) were also investigated. Major endocardial damage, characterized by the simultaneous presence of both anatomical and functional valvular involvement (AFVI), was observed in three patients with valvular vegetations and in five patients with combined valvular stenosis and/or regurgitation. Nine patients showed only an anatomic valvular involvement (AVI), expressed by a thickening of one or more valvular leaflets, without echo-Doppler findings of valvular dysfunction. Occurrence of major valvular involvement appears to be correlated with both longer disease duration (9.8 +/- 5.6 yrs in AFVI group vs 5.7 +/- 5.6 yrs in the remaining SLE patients; p < 0.001) and IgG aCL (chi-square = 5.546; p < 0.05). Left ventricular systolic function, evaluated by two-dimensional echocardiographic ejection fraction, was preserved in all patients (EF: 60 +/- 5%). Left ventricular diastolic function, as expressed by echo-Doppler transmitral flow indices of left ventricular filling, was subclinically impaired in 23 patients: only disease duration was significantly longer in these patients (7.7 +/- 5.9 yrs vs 4.9 +/- 4.8 yrs; p < 0.05). Our study demonstrated that cardiac involvement is quite frequent in SLE patients: the disease duration affects both endocardial and myocardial involvement; the anticardiolipin antibodies appear to be related to endocardial but not to myocardial damage.
Adolescent↗
Adenosine receptors on human leukocytes. IV. Characterization of an A1/Ri receptor.
Adenosine (10(-9)-10(-6) mol/l) and R-phenylisopropyladenosine (10(-9)-10(-7) mol/l) partially inhibited the intracellular accumulation of cyclic AMP induced by isoproterenol, prostaglandin E1, histamine and 5'-N-ethylcarboxamidoadenosine in lymphocytes. In contrast, S-phenylisopropyladenosine, which is a poor agonist of the adenosine A1/Ri receptor, had essentially no inhibitory effect. 8-Phenyltheophylline, in low concentrations that do not inhibit cyclic AMP phosphodiesterase, completely blocked the inhibitory effect of R-phenylisopropyladenosine on the increase in cyclic AMP induced by prostaglandin E1. R-Phenylisopropyladenosine (10(-8)-10(-6) mol/l) also inhibited the cyclic AMP accumulation in lymphocytes induced by forskolin (10(-5) mol/l), which activates adenylate cyclase through direct interaction with the enzyme. We also investigated the presence of the adenosine A1/Ri receptor on human polymorphonuclear leukocytes. R-Phenylisopropyladenosine (3 x 10(-9)-10(-7) mol/l) abolished the stimulating effects of prostaglandin and forskolin on cyclic AMP accumulation in polymorphonuclear leukocytes. This effect was blocked by 8-phenyltheophylline and was not observed with the stereoisomer S-phenylisopropyladenosine. The results support the existence of an A1/Ri receptor that regulates cyclic AMP metabolism of human lymphocytes and polymorphonuclear leukocytes.
Adenylyl Cyclases↗
Anti-inflammatory effect of cyclosporin A on human skin mast cells.
We have examined the effects of cyclosporin A (CsA) and cyclosporin H (CsH), which bind with different affinity to cyclophilin, to evaluate the role of this protein in the release of preformed (histamine) and de novo synthesized (prostaglandin D2[PGD2]) mediators of inflammatory reactions from human skin mast cells (HSMC). CsA (2.4-800 nM)-inhibited (5-60%) histamine release from HSMC challenged with anti-IgE. CsA exerted little, if any, inhibitory effect on histamine release from HSMC challenged with compound A23187 and substance P, whereas it completely suppressed A23187-induced histamine release from human basophils. Inhibition of histamine release from HSMC challenged with anti-IgE was extremely rapid and was not abolished by washing (three times) the cells before anti-IgE challenge. CsA (2.4-800 nM) markedly inhibited (25-70%) the de novo synthesis of PGD2 from HSMC challenged with anti-IgE. CsH, which has an extremely low affinity for cyclophilin, had no effect on skin mast-cell mediator release. These data suggest that CsA is a potent anti-inflammatory agent acting on HSMC, presumably by interacting with cyclophilin.
Anti-Inflammatory Agents↗
Anti-inflammatory effect of FK-506 on human skin mast cells.
FK-506 and the structurally related macrolide rapamycin are high-affinity ligands for a specific binding protein (FK-506 binding protein). We examined the effects of FK-506 and rapamycin on the release of pre-formed (histamine) and de novo synthesized inflammatory mediators (prostaglandin D2) from mast cells isolated from human skin tissue. FK-506 (0.1 to 100 nM) concentration-dependently inhibited (5 to 65%) histamine release from skin mast cells activated by anti-IgE. FK-506 was more potent in skin mast cells than in basophils (IC40 = 2.15 +/- 0.78 nM versus 5.12 +/- 1.34 nM; p < 0.001), whereas the maximal inhibitory effect was higher in basophils than in skin mast cells (88.77 +/- 2.44% versus 67.30 +/- 3.98%; p < 0.01). FK-506 had little or no inhibitory effect on histamine release from skin mast cells challenged with compound A23187 and substance P, respectively, whereas it completely suppressed A23187-induced histamine release from basophils. FK-506 (0.1 to 100 nM) also inhibited (up to 65%) the de novo synthesis of prostaglandin D2 from skin mast cells challenged with anti-IgE. Despite its structural similarity to FK-506, rapamycin (10 to 300 nM) had little or no effect on the release of histamine from skin mast cells induced by anti-IgE, A23187, and substance P. However, rapamycin competitively antagonized the inhibitory effect of FK-506 on anti-IgE-induced histamine release from skin mast cells with a dissociation constant of about 14 nM. These data indicate that FK-506, but not rapamycin, is a potent anti-inflammatory agent acting on skin mast cells presumably by binding to the FK-506 binding protein. It thus appears that binding to the FK-506 binding protein is necessary, but not sufficient, to deliver an inhibitory signal to skin mast cells.
Anti-Inflammatory Agents, Non-Steroidal↗
Human basophil/mast cell releasability. IX. Heterogeneity of the effects of opioids on mediator release.
Opioids differ in their capacity to cause release of histamine. The effects of increasing concentrations of three opioids (morphine, buprenorphine, and fentanyl) were studied on the release of preformed (histamine and tryptase) and de novo synthesized (prostaglandin D2 [PGD2] and peptide-leukotriene C4 [LTC4]) chemical mediators from human peripheral blood basophils and mast cells isolated from skin tissues or lung parenchyma. Basophils released < 5% of their histamine content and did not synthesize significant amounts of LTC4 when incubated with any of the opioids. Mast cells showed markedly different responses to the three opioids. Morphine (10(-5)-3 x 10(-4) M), in a concentration-dependent manner, induced histamine and tryptase release from skin but not from lung mast cells, up to a maximum of 18.2 +/- 1.9% and 13.0 +/- 4.1 micrograms/10(7) cells, respectively. Morphine did not induce de novo synthesis of PGD2 from skin mast cells. Buprenorphine (10(-6)-10(-4) M), in a concentration-dependent manner, caused histamine and tryptase release from lung but not from skin mast cells, to a maximum of 47.6 +/- 7.2% and 35.1 +/- 13.6 micrograms/10(7) cells, respectively. Buprenorphine also induced de novo synthesis of PGD2 and LTC4 from lung mast cells. Fentanyl (10(-5)-10(-3) M) did not induce histamine and tryptase release or the de novo synthesis of PGD2 or LTC4 from any mast cells. Histamine release caused by buprenorphine from lung mast cells was slow (t1/2 = 11.2 +/- 3.6 min) compared with that induced by morphine from skin mast cells (t1/2 < 1 min, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Basophils↗
Activation of human mast cells and basophils by general anaesthetic drugs.
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Anaphylaxis↗
Maitotoxin, a novel activator of mediator release from human basophils, induces large increases in cytosolic calcium resulting in histamine, but not leukotriene C4, release.
Maitotoxin (MTX) is a potent marine toxin which stimulates several Ca(++)-dependent processes presumably through an increase in Ca++ permeability. We have examined the effect of MTX on the release of chemical mediators from human basophils and its mechanism of action. MTX (1-20 ng/ml) induced histamine release (37-100%) from both mixed leukocyte preparations and purified basophils. Histamine release activated by MTX was slow (t 1/2 approximately equal to 15 min), temperature and Ca++ dependent (optimal at 37 degrees C and 1-2.5 mM Ca++). Sr++ ion could substitute for Ca++ in the secretory process. Digital video microscopy analysis of purified (> 70%) basophils revealed that MTX (1-20 ng/ml) induced a slow and marked increase of cytosolic Ca++ levels that was temporally coincident with histamine release. MTX (1-20 ng/ml) stimulated the release of sulfidopeptide leukotriene C4 from mixed leukocyte preparations (approximately equal to 0.5% basophils). However, purified basophils (77 +/- 7%) showed no sulfidopeptide leukotriene C4 release even in the presence of large histamine secretion (84 +/- 14%). Two organic Ca(++)-channel entry blockers, verapamil and diltiazem (1-30 microM) inhibited the release of histamine induced by MTX, whereas the dihydropyridine nifedipine (0.1-10 microM) caused only minimal inhibition. These results suggest that MTX represents a novel stimulus useful to study the role of Ca++ in human basophil mediator release.
Basophils↗