Anaphylactic Histamine Release Research Articles

Damnacanthal inhibits the NF-κB/RIP-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase

Damnacanthal is a major constituent of Morinda citrifolia L. (noni) and exhibits anti-cancer and anti-inflammatory activities. However, the effects of damnacanthal on allergic diseases have not been determined. In this study, we investigated the effect of damnacanthal on mast cell-mediated allergic inflammatory responses. Damnacanthal significantly and dose-dependently inhibited compound 48/80-induced systemic anaphylactic shock, histamine release and intracellular calcium levels. In particular, IgE-mediated passive cutaneous anaphylaxis was significantly inhibited by the oral administration of damnacanthal. In addition, we report for the first time that p56lck tyrosine kinase was expressed in phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated mast cells. Furthermore, damnacanthal inhibited the up-regulation of p56lck tyrosine kinase activity by PMACI and repressed PMACI-induced histidine decarboxylase expression and activity. Damnacanthal also inhibited PMACI-induced interleukin (IL)-1β, IL-6 and tumor necrosis factor-α expressions by suppressing nuclear factor-kappa B (NF-κB) activation and suppressed the activation of caspase-1 and the expression of receptor interacting protein-2. This study shows damnacanthal inhibits the NF-κB/receptor-interacting protein-2/caspase-1 signal pathway by inhibiting p56lck tyrosine kinase and suggests that damnacanthal has potential for the treatment of mast cell-mediated allergic disorders.

Effect of leaves of Eriobotrya japonica on anaphylactic allergic reaction and production of tumor necrosis factor-α

Leaves of Eriobotrya japonica Lindl. (Rosaceae) (LEJL) have been used as traditional medicines for inflammatory diseases and chronic bronchitis. However, its effect on mast cell-mediated anaphylactic reaction is not known. The anaphylactic allergic reaction is involved in many allergic diseases such as asthma and allergic rhinitis. In this report, we investigate the effect of LEJL on the anaphylactic allergic reaction and studied its possible mechanisms of action. LEJL inhibited compound 48/80-induced systemic anaphylactic reactions and serum histamine release in mice. LEJL dose-dependently decreased the IgE-mediated passive cutaneous anaphylaxis and histamine release from mast cells. Furthermore, LEJL decreased the production of tumor necrosis factor-α in phorbol 12-myristate 13-acetate and A23187-stimulated human mast cells. These findings provide evidence that LEJL could be a candidate as an anti-allergic agent.

Mast cell renin and a local renin-angiotensin system in the airway: role in bronchoconstriction.

We previously reported that mast cells express renin, the rate-limiting enzyme in the renin-angiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin I-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG II) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG II type 1 receptors (AT(1)R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG II-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT(1)R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and beta-hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway renin-angiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG II is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease.

Antianaphylactic Properties of 7-Epiclusianone, a Tetraprenylated Benzophenone Isolated from Garcinia brasiliensis

Prior studies have emphasized the anti-inflammatory and antioxidant properties of polyisoprenylated benzophenone derivatives, but their putative effect on allergic conditions has not yet been addressed. In the current study, the naturally occurring 7-epiclusianone, isolated from Garcinia brasiliensis, was investigated to check its effectiveness on allergen-evoked intestinal spasm. The standard antiallergic azelastine was used for comparison. We found that 7-epiclusianone and azelastine inhibited antigen-induced contractions of guinea pig ileum with similar IC (50) values (2.3 +/- 1.1 microM and 3.3 +/- 1.2 microM, respectively). A similar blockade of anaphylactic histamine release from the ileum was also noted. In contrast, azelastine was more potent than 7-epiclusianone to prevent spasms induced by histamine (IC (50) = 6.3 +/- 0.2 nM and 3.7 +/- 0.1 microM, respectively). These findings reveal that 7-epiclusianone is clearly active against the anaphylactic response and should be considered as a molecular template in drug discovery for allergic syndromes.

Cardiac anaphylaxis: Pathophysiology and therapeutic perspectives

Cardiac anaphylaxis refers to the functional and metabolic changes in the heart caused by the anaphylactic release of histamine and vasoactive products of arachidonic acid cascade by mast cells and basophils. As in most type I hypersensitivity-based diseases, histamine plays a key role in the pathophysiology of cardiac anaphylaxis. In the heart, mast cell activation and histamine release are controlled by multiple endogenous mechanisms, including adrenergic neural control, histamine-dependent negative feedback operated through H2 receptors, and the endogenous generation of nitric oxide (NO) and carbon monoxide (CO). All these mechanisms can be targeted by substances that have revealed a clear-cut effect in blunting cardiac anaphylaxis in experimental animal models, and could be developed as potential, novel anti-anaphylactic drugs. In this article, we discuss new findings and significant trends related to this topic.

Adoptive Transfer of Mast Cells Abolishes the Inflammatory Refractoriness to Allergen in Diabetic Rats

Mast cells are pivotal secretory cells primarily implicated in allergen-evoked inflammatory responses and are downregulated following experimental chemical diabetes. Here we tested the hypothesis that a decrease in the number and reactivity of mast cells would account for the hyporesponsiveness of diabetic rats to allergen-induced inflammation. We found that the anaphylactic release of histamine from sensitized ileum, trachea and skin tissues was clearly reduced in rats turned diabetic via intravenous administration of alloxan. Likewise, actively and passively sensitized diabetic rats mounted a weaker allergen-evoked pleural mast cell degranulation and protein extravasation, as compared to sensitized nondiabetic animals, which paralleled a marked reduction in the mast cell population in the pleural cavity. The number of mast cells enumerated in the mesentery from diabetic rats was also clearly reduced. The allergen-evoked plasma leakage in diabetic rats was restored by the transfer of mast cells from sensitized nondiabetic rats. Moreover, the adoptive transfer of sensitized mast cells from diabetics to naive animals led to a lower allergen-induced exudation as compared to the response noted after the transfer of sensitized naive mast cells. Purified mast cells from diabetic rats were hyporesponsive to antigen and compound 48/80 stimulation in vitro as attested by histamine release. Thus, our results show that the phenomenon of refractoriness of diabetic animals to allergen challenge appears to be accounted for by a reduction in the number and reactivity of mast cells.

A plant histaminase modulates cardiac anaphylactic response in guinea pig

The effect of a copper amine oxidase (histaminase) purified from the pea seedling as free or immobilized enzyme on the response to specific antigen was studied in isolated hearts from actively sensitized guinea pigs. In vitro challenge with the specific antigen of hearts from actively sensitized animals evokes a positive inotropic and chronotropic effect, a coronary constriction, followed by dilation and an increase in the amount of histamine and nitrites, the oxidation product of nitric oxide, in the perfusates. In the presence of both forms of histaminases, the positive inotropic and chronotropic responses as well as the coronary constriction and the release of histamine were fully blocked. The amount of nitrites, appearing in the perfusates when anaphylaxis is elicited in the presence of both forms of histaminases, is significantly increased, as well as nitric oxide synthase activity and cyclic GMP content in cardiac tissue, while cardiac calcium overload was significantly prevented. These observations demonstrate that the decrease in the anaphylactic release of histamine and the subsequent abatement of the cardiac response to antigen can be accounted for by the inactivation by histaminase of the released histamine and by a stimulation of endogenous nitric oxide production.

L-Ephedrine is a major constituent of Mao-Bushi-Saishin-To, one of the formulas of Chinese medicine, which shows immediate inhibition after oral administration of passive cutaneous anaphylaxis in rats.

Whether Mao-Bushi-Saishin-To (MBST), one of the formulas of classical Chinese medicine, is effective on 48-h passive cutaneous anaphylaxis (PCA) in rats and which substance in the formula is responsible for its inhibitory action were examined. In the studies on PCA, MBST (hot water extract of the whole herbal formula), extracts of Ephedra herb (Mao), l-ephedrine and other reference drugs were orally administered immediately or at various times before or 5 min after the antigen challenge. In the experiments on anaphylactic histamine release from rat peritoneal mast cells, l-ephedrine and d-pseudoephedrine were added at 10(-4)-10(-7) g/ml at 30, 10, 3 or 0 min before antigen provocation. The time course study indicated that MBST produced a prompt and long lasting inhibition of PCA. Among the constituents of Mao, l-ephedrine exerted this prompt inhibitory activity, but d-pseudoephedrine did not. Neither pseudoephedrine nor l-ephedrine prevented the anaphylactic histamine release from isolated peritoneal mast cells. It is strongly emphasised that the rapid suppression of PCA by orally administered l-ephedrine must be exerted by a mechanism distinct from that of suppression produced following gastrointestinal absorption of the drug, because the time required for the inhibition was extraordinarily short. However, direct inhibition of anaphylactic histamine release from isolated mast cells was excluded in this inhibition of PCA.

Suppression of Immunoglobulin E-Mediated Anaphylactic Reaction by Alpinia Oxyphylla in Rats

We investigated the effect of Alpinia oxyphylla water extract (AOWE) on immunoglobulin E (IgE)-mediated anaphylaxis activated by anti-dinitrophenyl (DNP) IgE antibody. AOWE dose-dependently suppressed passive cutaneous anaphylaxis (PCA) when intraperitoneally or orally administered. On the other hand, it showed weak suppressive activity when administred intravenously. AOWE dose-dependently suppressed anaphylactic histamine release from rat peritoneal mast cells (RPMC) activated by anti-DNP IgE antibody. However, AOWE had a significant augmenting effect on anti-DNP IgE antibody-induced tumor necrosis factor-α secretion from RPMC. These results indicated that AOWE may possess strong antianaphylactic action and also suggest that differential activity following administration routes may be caused by difference of bioavailability.

P–667 - Effects of stress on passive cutaneous anaphylaxis in rats and anaphylactic histamine release from the skin.

P–667 - Effects of stress on passive cutaneous anaphylaxis in rats and anaphylactic histamine release from the skin.

Effect of TYB-2285 on Peritoneal Anaphylaxis in Passively Sensitized Rats

1. The effect of TYB-2285, a novel anti-inflammatory drug, was investigated on passive peritoneal anaphylaxis in rats, and compared with disodium cromoglycate (DSCG), amlexanox, ketotifen fumarate and tranilast. 2. As parameters of passive peritoneal anaphylaxis, histamine release into the peritoneal cavity and capillary permeability elicited by ascitis were measured. 3. TYB-2285 (10 mg/kg), when given intraperitoneally at 0.5, 1 and 2 min before antigen challenge, inhibited anaphylactic histamine release by 36.2%, 57.5% and 52.6%, respectively. TYB-2285 also inhibited capillary permeability by 20.9%, 57.6% and 49.0%, respectively. 4. DSCG (10 mg/kg), given intraperitoneally 0.5 min before challenge, inhibited histamine release and capillary permeability by 79.6% and 57.6%, respectively. 5. Amlexanox (10 mg/kg), given intraperitoneally 0.5 min before challenge, inhibited histamine release and capillary permeability by 85.6% and 74.8%, respectively. 6. A time-course study showed that TYB-2285 (30 mg/kg) was effective for 30 min after oral administration. A dose–response study suggested that the inhibitory effect of TYB-22585 (postoperatively) on histamine release during PPA reached a plateau at 10 mg/kg. 7. In passive peritoneal anaphylaxis in vitro, TC-1121 and TC-1122, metabolites of TYB-2285, inhibited antigen-induced histamine release at 10 −7 to 10 −5 M in a dose-dependent manner, whereas TYB-2285 itself and other major metabolites of TYB-2285, TC-286 and TC-326, did not inhibit histamine release, even at 10 −4 M.

Suppression of immunoglobulin E-mediated anaphylactic reaction by Hwanglyun-Haedok-Tang water extract

According to traditional Oriental philosophy, Hwanglyun-Haedok-Tang (HH-Tang) is a prescription for heat clearing of the organism. This prescription has been used against allergic diseases for generations, and still occupies an important place in traditional medicine in Korea. In this study, we investigated the effect of HH-Tang water extract on immunoglobulin E (IgE)-mediated anaphylaxis activated by anti-dinitrophenyl (DNP) IgE antibody. HH-Tang water extract potently suppressed passive cutaneous anaphylaxis (PCA) when intradermally, intraperitoneally, or orally administered. On the other hand, it showed weak suppressive activity when administered intravenously. HH-Tang water extract, dose-dependently suppressed anaphylactic histamine release from rat peritoneal mast cells (RPMC) activated by anti-DNP IgE antibody. Moreover, HH-Tang water extract had a significant suppressive effect on anti-DNP IgE antibody-induced tumor necrosis factor- α secretion from RPMC. The level of cAMP in RPMC, when HH-Tang water extract was added, significantly increased compared with that of normal control. These results indicate that HH-Tang water extract may possess strong antianaphylactic action and also suggest that differential activity following administration routes may be caused by difference of bioavailability.

Effects of histamine agonists and antagonists on rat peritoneal mast cells.

histamine release from rat peritoneal mast cells (RPMC). Since inhibitory effects of these compounds could be reversed by thioperamide, but not by mepyramine or cimetidine, an H3-receptor dependent negative feedback mechanism on anaphylactic histamine release was proposed to exist in RPMC. However since dimaprit has no H3receptor stimulating activity in rat brain [3], these authors suggested that the postulated H3-receptors in mast cells are a subtype distinct from those in the brain. In contrast, Lau and Pearce [4] reported that dimaprit and another H2 agonist impromidine had no inhibitory activity on RPMC at concentrations <10 π5 M but instead induced histamine release at higher concentrations. Hence, we reinvestigated the effects of dimaprit and impromidine, and included the H3 agonist imetit for comparison. The effects of these three compounds on RPMC were further characterised with specific histamine receptor antagonists and benzalkonium chloride.

GABA-mediated inhibition of the anaphylactic response in the guinea-pig trachea.

1. In sensitized guinea-pigs, the effects of gamma-aminobutyric acid (GABA) and GABAmimetic drugs have been investigated on tracheal segments contracted by cumulative application of an allergen (ovoalbumin, OA) and on serosal mast cells. The same drugs have also been tested on activation of alveolar macrophages isolated from unsensitized guinea-pigs. 2. Superfusion with GABA (1-1000 microM) reduced the contraction intensity of tracheal strips. The effect of GABA (100 microM) was not affected by the carrier blockers, nipecotic acid and beta-alanine (300 microM each). It was mimicked by the GABAB agonist (-)-baclofen (100 microM) but not 3-aminopropanephosphinic acid (100 microM, 3-APA). The GABAA agonist, isoguvacine (100 microM) did not exert any effect. GABA (10 microM)-induced inhibition of tracheal contractions was reduced by the GABAB antagonist, 2-hydroxysaclofen (100 microM, 2-HS), but not by the GABAA antagonist, bicuculline (30 microM). 3. The reduction in contraction intensity induced by GABA (100 microM) was prevented by a 40 min preincubation of tracheal strips with capsaicin (10 microM), but not tetrodotoxin (TTX, 0.3 microM). The effect of GABA (1000 microM) was absent after preincubation with indomethacin (2.8 microM) but unmodified when nordihydroguaiaretic acid (NDGA, 3.3 microM) was used. Finally, removal of the epithelium prevented the GABA effect. 4. Anaphylactic histamine release from serosal mast cells isolated from sensitized animals was not affected either by GABA (10-1000 microM) or the selective receptor agonists (-)-baclofen (0.1-1000 microM) and isoguvacine (10-1000 microM). The release of platelet-activating factor (PAF) from alveolar macrophages stimulated by formyl-Met-Leu-Phe (FMLP; 1 microM) was modified neither by GABA (100 microM)nor by (-)-baclofen (100microM).5. In conclusion, these data show that GABA can inhibit allergic phenomena in the guinea-pig airways through activation of GABAB receptors. An involvement of neuropeptidergic sensory structures is suggested but a role for epithelial cells and arachidonate metabolites is not definitely proved.

Two-phase increment of Ca2+ uptake, intracellular Ca2+ concentration, and histamine release following antigen stimulation in mouse bone marrow-derived mast cells (BMMC).

The relationship between the influx of Ca2+ into cells or cytosolic Ca2+ concentration ([Ca2+]i) and the histamine release following antigen stimulation in mouse bone marrow-derived mast cells (BMMC) was examined, and the results were compared with those from human lung mast cells (HLMC) and rat peritoneal mast cells (RPMC) in some experiments. Anaphylactic histamine release from BMMC as well as HLMC, but not that from RPMC, was dependent on the extracellular Ca2+. When BMMC were challenged by antigen following radioactive 45Ca2+ addition, two phases of 45Ca2+ influx into the cells were observed. The first phase, which was initiated and completed within 30 sec and 2 min, respectively, after antigen treatment, appeared to be related to anaphylactic histamine release. The second influx began 30 sec subsequent to the first one and lasted for at least 2 min, and this occurred after the completion of the histamine release; So far, it is not known how this second influx participates in the intracellular event(s). On the other hand, only one sustained elevation of [Ca2+]i occurred that reached its maximum within 2 min after antigen stimulation. Following stimulation of BMMC with antigen in the absence of Ca2+, Ca2+ addition 1 to 5 min later time-dependently enhanced the histamine release, although the release was deteriorated by further extension of Ca2+ addition. In contrast, the releasability of HLMC was rapidly decreased. These results indicate that extracellular Ca2+ not only is prerequisite for anaphylactic histamine release from BMMC, but also may modulate the release and participate in some intracellular event(s) which has yet to be focused upon.

Possible participation of histamine H3-receptors in the regulation of anaphylactic histamine release from isolated rat peritoneal mast cells.

Anaphylactic histamine release from isolated rat peritoneal mast cells was concentration-dependently blocked by a 5-min treatment with exogenous histamine at 0.9 and 9 microM and enhanced by a 20- to 30-min treatment with thioperamide (H3-antagonist) at 3 microM with significance, but little affected by mepyramine (H1-antagonist) and cimetidine (H2-antagonist) at the cell concentration of 10(6) mast cells/ml. At a low concentration of mast cells (10(4) mast cells/ml), (R)-alpha-methylhistamine (alpha-MH), an H3-agonist, at 0.9-90 microM also inhibited the release in a concentration-dependent fashion. Thioperamide, but neither mepyramine nor cimetidine, significantly restored the decreased release by alpha-MH. However, the complete restoration by thioperamide could not be achieved because the drug itself slightly but concentration-dependently inhibited anaphylactic histamine release. On the other hand, not only betahistine and dimaprit but also alpha-MH did not suppress histamine release from the mast cells induced by compound 48/80. In rat plasma, considerable levels of histamine were detected. From these results, it is strongly suggested that histamine H3-like receptors are largely responsible for the negative feedback regulation of the anaphylactic histamine release from rat peritoneal mast cells.

Salmeterol inhibits anaphylactic histamine release from guinea-pig isolated mast cells.

Salmeterol (1 nM-100 microM) showed an inhibitory action on anaphylactic histamine release from mast cells, isolated from pleural and peritoneal cavities of actively sensitized guinea-pigs and stimulated by incubation with allergen. The effect is concentration-dependent and is reduced by the beta-adrenoceptor antagonist propranolol (1 microM). This study supports the hypothesis of an anti-inflammatory property of salmeterol, which concerns cells involved in the early phases of asthma.

Antiallergic effects of ZCR-2060: effect on allergic cutaneous reactions and rhinitis models in mice and rats.

The antiallergic action of 2-[2-[4-(diphenylmethyl)-1-piperadinyl] ethoxy] benzoic acid maleate (ZCR-2060) was investigated on allergic cutaneous reactions and nasal vascular permeability in mice and rats. ZCR-2060 markedly inhibited immediate allergic cutaneous reactions, including passive cutaneous anaphylaxis (PCA) in rats and mice; histamine-, compound 48/80- and calcium ionophore A 23187-induced cutaneous reactions in rats; and biphasic skin reactions mediated by monoclonal IgE antibody and epicutaneous challenge with antigen in mice, but did not affect 5-hydroxytryptamine-induced cutaneous reaction in rats. The antigen-induced nasal vascular permeability increase in actively and passively sensitized rats and histamine-induced nasal vascular permeability increase in rats (allergic rhinitis model) were clearly inhibited in a dose-dependent fashion by ZCR-2060. Moreover, ZCR-2060 significantly inhibited antigen-induced anaphylactic histamine release from rat peritoneal mast cells and carrageenin-induced paw edema in rats. These results suggest that ZCR-2060 has antiallergic effects on allergic cutaneous reactions and experimental rhinitis, probably due to histamine H1-receptor blockage and the inhibition of histamine release.

Involvement of β-Adrenergic Systems in the Antagonizing Effect of Paeoniflorin on the Scopolamine-Induced Deficit in Radial Maze Performance in Rats

Whether anaphylactic histamine release from rat peritoneal mast cells is influenced by betahistine, a histamine H1-receptor agonist/H3-antagonist, and dimaprit, an H2-agonist, was examined. Treatment with dimaprit at 6 and 60 microM for 20 min significantly inhibited the anaphylactic histamine release, whereas betahistine at up to 80 microM under the same conditions did not affect it. Treatment with dimaprit at 6 and 60 microM for 1 to 20 min and for 5 to 20 min, respectively, caused a time-dependent inhibition of the release, but up to 30 min treatment with 8 and 80 microM betahistine had no effect. The decreased histamine release induced by dimaprit was recovered by neither mepyramine nor cimetidine. However, thioperamide, an H3-selective antagonist, dose-dependently restored the diminished release. From these results, the inhibition of anaphylactic histamine release by dimaprit is not produced by the stimulation of H2-receptors, but involves the stimulation of H3-like receptors or H3-subtype receptors, which are distinct from the H3-receptors located in brain, and suggests that the receptor plays an important role in the negative feedback regulation of histamine release.

Dimaprit, a Histamine H2-Agonist, Inhibits Anaphylactic Histamine Release from Mast Cells and the Decreased Release Is Restored by Thioperamide (H3-Antagonist), but Not by Cimetidine (H2-Antagonist)

The effects of lacidipine (LC), a new dihydropyridine calcium antagonist, were studied in comparison with those of nifedipine (NF) in isolated arteries of the dog (DG-AR) and isolated aorta (GP-AO), left and right atria (GP-LA, GP-RA) and ventricular papillary muscles (GP-PM) of the guinea pig. In DG-AR precontracted with high K+, LC and NF produced a concentration-dependent relaxation. The relaxant effect of LC was most potent in the basilar artery. The calcium antagonistic effects of LC was 8.7 and 2.1 times more potent than those of NF, in GP-AO and GP-LA, respectively. Thus, LC was about 4 times more selective towards vascular smooth muscles than NF. The negative chronotropic effects in GP-RA and the negative inotropic effect in GP-PM of NF were more pronounced than those of LC. NF was more potent in inhibiting the action potential of GP-PM than LC both in normal polarized and depolarized conditions. The effects of LC were long-lasting. These results suggest that LC is a potent, highly vascular-selective calcium antagonist with little cardiodepressant effects and as such may be suitable for the treatment of hypertension.