calcimycin and Hypersensitivity

Immunologic or calcium-dependent activation of proteolytically dispersed human lung cells containing 5% mast cells causes the release of large amounts of PGD2 and TxB2. In cell purification experiments, only those fractions containing mast cells had the capacity to generate PGD2 and release histamine with IgE-dependent activation. The cells of origin of T X B2 are likely to be cells of the monocyte-macrophage series, although additional eicosanoid release may occur from immunologically activated lymphocytes and eosinophils. In men who have asthma, inhalation of low concentrations of PGD2 results in bronchoconstriction, whereas higher concentrations of PGD2 are needed to produce bronchoconstriction in normal subjects. Subjects with asthma exhibited 3.5-fold greater responsiveness to inhaled PGD2 than to PGF2 alpha. These observations demonstrate that PGD2 is the most potent bronchoconstrictor prostanoid tested in man. In both normal subjects and subjects with asthma, a single inhalation of PGF2 alpha resulted in a doubling in plasma levels of 13,14-dihydro-15-keto-PGF2 alpha. Plasma levels of this metabolite did not change after PGD2 inhalation. These results indicate that the 11-keto reduction of PGD2 to PGF2 alpha with subsequent inactivation is not important in the initial metabolism of PGD2.

Topics: Airway Resistance; Animals; Antibodies, Anti-Idiotypic; Asthma; Calcimycin; Cells, Cultured; Epoprostenol; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Lung; Prostaglandins; Thromboxane A2

Platelets-isolated or in conjunction with leukocytes-interact with vessel walls in many experimental and human diseases. Several mediators are held responsible for platelet activation and interaction with leukocytes, among which PAF-acether (platelet-activating factor) is a prime candidate. This phospholipid mediator is released by most inflammatory cells, including neutrophils, by isolated organs such as kidney and heart, is a potent platelet and neutrophil agonist, and exerts major vasoactive properties. Its biosynthesis involves a two-step enzymatic process yielding the active molecule from the membrane alkyl-ether choline-containing phospholipids. The first step implicates a phospholipase A2 that hydrolyzes a long-chain fatty acid (which can be arachidonic acid) from membrane phospholipids, leaving the intermediate compound lyso PAF-acether, a PAF-acether precursor that is acetylated by an acetyltransferase in a second step. It can also result from deacetylation of PAF-acether by an acetylhydrolase. PAF-acether release might explain the intervention of platelets in diseases such as glomerulonephritis and allergic vasculitis, in which the involvement of neutrophils and platelets is frequently noted. The end result of these complex sets of cell-to-cell interactions is the release of most known inflammatory mediators, influencing vascular permeability, cell infiltration, and smooth muscle contraction. Nevertheless, direct evidence for the implication of these rather well-defined cellular and molecular interactions in human pathologic states remains to be obtained.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Calcimycin; Humans; Hypersensitivity; Kidney Diseases; Platelet Activating Factor; Rabbits; Vascular Diseases

Preliminary studies in hematological patients have indicated that treatment with rhG-CSF reduces basophil releasability ex vivo. We examined this phenomenon further, in allergic patients. Ten patients with grass pollen rhinoconjunctivitis were given rhG-CSF (5 micrograms/kg/day s.c.) for 5 days, and examined before and after treatment. Basophil counts increased from 5 to 19 x 10(9)/l (P < 0.01). Total blood histamine increased from 80 to 160 micrograms/l (P < 0.01), corresponding to a decrease in average basophil histamine content from 1.5 to 0.81 pg/cell (P < 0.01). Isolated mononuclear cells showed a significantly decreased histamine release (HR) when stimulated with A23187 and grass. Whole blood experiments showed a similar decreased HR to grass and anti-IgE (P < 0.01). However, we found an increase in total blood histamine. We conclude that treatment with rhG-CSF (1) increases the number of circulating blood basophils, (2) reduces the average histamine content per basophil, and (3) reduces the basophil releasability. These findings could be due to the mobilization of immature basophils from the bone marrow.

Topics: Adult; Basophils; Calcimycin; Granulocyte Colony-Stimulating Factor; Histamine Release; Humans; Hypersensitivity; In Vitro Techniques; Leukocyte Count; Middle Aged; Pollen; Recombinant Proteins; Rhinitis, Allergic, Seasonal

Zanthoxylum piperitum (ZP, 'Japanese pepper') is a traditional medicine and pepper used in Asian countries such as Japan. Hydroxy-α-sanshool, a pungent-tasting substance contained within ZP, has been reported to slightly suppress immunoglobulin E (IgE)-mediated mast cell degranulation. The current study aims to newly identify anti-allergic compounds derived from ZP. We examine the inhibitory mechanisms behind IgE-mediated mast cell degranulation. By inhibitory effect-guided isolation, we identified degranulation inhibitory compounds derived from ZP fruit: 1-acetoxy-7-hydroxy-3, 7-dimethylocta-2E, 5E-diene (ZP1) and 8-hydroxygeranyl acetate (ZP2). ZP1 and ZP2 inhibited IgE-mediated degranulation and A23187-mediated degranulation in RBL-2H3 mast cells. Our findings suggest the inhibition of degranulation by ZP1 and ZP2 was by inhibition of Lyn phosphorylation, followed by inhibition of intracellular Ca

Topics: Animals; Anti-Allergic Agents; Calcimycin; Cell Degranulation; Cell Line; Cell Survival; Fruit; Hypersensitivity; Immunoglobulin E; Male; Mast Cells; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Passive Cutaneous Anaphylaxis; Rats; Zanthoxylum

micro-RNAs (miRNAs) are non-coding RNAs which play important role in human diseases. Dysregulated miRNAs have been identified in asthma patient while their precise roles in asthma are not well elucidated. We compared the expression level of total 11 miRNAs between PMA/A23187-treated and control HMC-1 mast cells. We determined the effect of miR-20a on inflammation by overexpressing miR-20a mimic or its antagonist. We further predicted histone deacetylase 4 (HDAC4) as potential target of miR-20a and explored the effects of miR-20a on HDAC4 expression and histone modification. miR-20a was down-regulated in PMA/A23187-treated HMC-1 cells. miR-20a inhibited expression of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and Interferon gamma (IFN-γ) while promoted Interleukin 10 (IL-10) production. miR-20a targeted HDAC4 and suppressed its expression, which contributed to epigenetically regulation of IL-10 expression by miR-20a. hsa-miR-20a-5p attenuates allergic inflammation in HMC-1 cells by targeting HDAC4.

Topics: Base Sequence; Calcimycin; Cell Line; Cytokines; Down-Regulation; Epigenesis, Genetic; Histone Deacetylases; Humans; Hypersensitivity; Inflammation; Inflammation Mediators; MicroRNAs; Ovalbumin; Repressor Proteins; Tetradecanoylphorbol Acetate

Basophils (BAs) are the least common granulocytes of all leukocytes, but they play an important role in orchestrating of chronic allergic inflammation. The Notch signaling pathway is a highly conserved pathway that influences cell lineage decisions and differentiation during various stages of development. However, the relationship between Notch signaling and BA remains to be elucidate. Here, we report that several Notch signaling molecules were found to be expressed in BAs. γ-secretase inhibitor (GSI) treatment increase BAs apoptosis, and suppress BAs proliferation. Furthermore, GSI reduced BAs in the S phase, with a concomitant accumulation in G1 and G2 phases. In addition, GSI also significantly down-regulated mRNA levels of cytokines IL-4, IL-6 and IL-13 induced by A23187, and this effect was dependent on MAPK pathway. Finally, IL-6 inhibition was specifically associated with ERK and IL-13 with JNK. Therefore, Notch signaling regulates BA biological function, at least partially via the modulation of MAPK.

Topics: Animals; Basophils; Calcimycin; Cell Cycle; Cells, Cultured; Chronic Disease; Cytokines; Extracellular Signal-Regulated MAP Kinases; Hypersensitivity; Inflammation; Inflammation Mediators; Mice; Oligopeptides; Receptors, Notch; Signal Transduction

Zinc (Zn) is an essential trace metal for eukaryotes. The roles of Zn in the numerous physiological functions have been elucidated. Bamboo salt contains Zn that was shown to have anti-inflammatory effect and other health benefits. Nanoparticles of various types have found application in the biology, medicine, and physics. Here we synthesized tetrapod-like, zinc oxide nanoparticles (ZO-NP; diameter 200 nm, source of Zn) using a radio frequency thermal plasma system and investigated its effects on mast cell-mediated allergic inflammatory reactions. ZO-NP was found to inhibit the productions and mRNA expressions of inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α on the phorbol 12-myristate 13-acetate plus A23187 (PMACI)-stimulated human mast cell line, HMC-1 cells. In these stimulated cells, caspase-1 and nuclear factor-κB activations were abolished by ZO-NP, and the expressions of receptor interacting protein2 (RIP2) and IκB kinaseβ (IKKβ) induced by PAMCI were reduced. On the other hand, ZO-NP alone increased the expressions of RIP2 and IKKβ in normal condition. ZO-NP inhibited the phosphorylation of extracellular signal-regulated protein kinase in the PMACI-stimulated HMC-1 cells. Furthermore, ZO-NP significantly inhibited passive cutaneous anaphylaxis activated by anti-dinitrophenyl IgE. These findings indicate that ZO-NP effectively ameliorates mast cell-mediated allergic inflammatory reaction, and suggest that ZO-NP be considered a potential therapeutic for the treatment of mast cell-mediated allergic diseases.

Topics: Animals; Anti-Inflammatory Agents; Calcimycin; Caspase 1; Cell Line; Cytokines; Enzyme Activation; Gene Expression Regulation; Humans; Hypersensitivity; I-kappa B Kinase; Inflammation; Male; Mast Cells; Mice; Mitogen-Activated Protein Kinases; Nanoparticles; NF-kappa B; Passive Cutaneous Anaphylaxis; Phosphorylation; Proteolysis; Receptor-Interacting Protein Serine-Threonine Kinase 2; RNA, Messenger; Tetradecanoylphorbol Acetate; Zinc Oxide

Cheongseoikki-tang (CIT, Korean), also called Qingshu Yiqi decoction () and Seisho-ekki-to (Japanese), is well known as an effective traditional combination of herbs for treating cardiovascular diseases. This study was to research its effects on bone marrow-derived mast cell (BMMC)-mediated allergy and inflammation mechanisms.. In this study, the biological effect of Cheongseoikki-tang ethanol extract (CITE) was evaluated, focusing on its effects on the production of allergic mediators by phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 (A23187)-stimulated BMMCs. These allergic mediators included interleukin-6 (IL-6), prostaglandin D2 (PGD2), leukotriene C4 (LTC4), and β-hexosaminidase (β-hex).. Our data revealed that CITE inhibited the production of IL-6, PGD2, LTC4, and β-hex induced by PMA plus A23187 (P<0.05).. These findings indicate that CITE has the potential for use in the treatment of allergy.

Topics: Animals; Anti-Inflammatory Agents; beta-N-Acetylhexosaminidases; Bone Marrow Cells; Calcimycin; Cell Degranulation; Cell Survival; Drugs, Chinese Herbal; Hypersensitivity; Interleukin-6; Leukotriene C4; Male; Mast Cells; Mice; Mice, Inbred BALB C; Prostaglandin D2; Tetradecanoylphorbol Acetate

The root of Angelica acutiloba is a widely used herbal medicine which has been used as a typical therapeutic for allergic diseases in traditional medicine. This study was aimed to investigate the effects of A. acutiloba on allergic reactions in in vitro and in vivo models and its mechanism of action. A. acutiloba was extracted by maceration with 80% ethanol (AAE) and standardized by high-performance liquid chromatography. We investigated the effect of AAE on phorbol-12-myristate-13-acetate plus calcium ionophore A23187 (PMACI)-induced cytokine release; phosphorylation of JNK, ERK, and p38 in human mast cell-1 (HMC-1); and compound 48/80-induced release of histamine in rat peritoneal mast cells (RPMCs). We also investigated the effects on Evans blue (EB) extravasation induced by anti-DNP IgE in rats. Treatment with 1, 10 and 100 μg/ml AAE concentration-dependently inhibited the release of cytokines (tumor necrosis factor-α, interleukin (IL) -6, and IL-8) and phosphorylation of ERK and JNK induced by PMACI in HMC-1 cells, but it did not inhibit the phosphorylation of p38. It also inhibited compound 48/80-induced histamine release in RPMCs. Oral administration of 271 mg/kg AAE inhibited EB extravasation in a passive cutaneous anaphylaxis rat model. In conclusion, AAE inhibited mast cell-derived allergic reactions by inhibiting the release of histamine, the production of pro-inflammatory cytokines, and the phosphorylation of ERK and JNK.

Topics: Angelica; Animals; Calcimycin; Calcium Ionophores; Carcinogens; Cell Line; Complex Mixtures; Cytokines; Extracellular Signal-Regulated MAP Kinases; Histamine Release; Humans; Hypersensitivity; Male; MAP Kinase Kinase 4; Mast Cells; Phosphorylation; Rats; Rats, Sprague-Dawley; Tetradecanoylphorbol Acetate

Cinnamomum cambodianum has been used as a traditional medicine in Cambodia. Its effect on the bone marrow-derived mast cells (BMMCs) mediated allergic response remains unknown. In this study, a chloroform-soluble extract of C. cambodianum was evaluated for its effect on allergic mediators, including prostaglandin D₂ (PGD₂), leukotriene C₄ (LTC₄), β-hexosaminidase and cyclooxygenase-2 (COX-2) protein, in phorbol 12-myristate 13-acetate (PMA) plus calcimycin-stimulated BMMCs. The results revealed that the chloroform-soluble extract inhibited the production of interleukin-6, PGD₂ and LTC₄, and the expression of COX-2 in PMA plus calcimycin-stimulated BMMCs, implying a potential benefit of C. cambodianum in the treatment of allergy.

Topics: Animals; Bone Marrow Cells; Calcimycin; Calcium Ionophores; Carcinogens; Chloroform; Cinnamomum; Complex Mixtures; Cyclooxygenase 2; Female; Gene Expression Regulation, Enzymologic; Hypersensitivity; Interleukin-6; Leukotriene C4; Mast Cells; Mice; Mice, Inbred BALB C; Prostaglandin D2; Tetradecanoylphorbol Acetate

Type I allergy is characterized by the release of granule-associated mediators, lipid-derived substances, cytokines, and chemokines by activated mast cells. To evaluate the anti-allergic effects of macelignan isolated from Myristica fragrans Houtt., we determined its ability to inhibit calcium (Ca(2+)) influx, degranulation, and inflammatory mediator production in RBL-2 H3 cells stimulated with A23187 and phorbol 12-myristate 13-acetate. Macelignan inhibited Ca(2+) influx and the secretion of β-hexosaminidase, histamine, prostaglandin E(2), and leukotriene C(4); decreased mRNA levels of cyclooxygenase-2, 5-lipoxygenase, interleukin-4 (IL-4), IL-13, and tumor necrosis factor-α; and attenuated phosphorylation of Akt and the mitogen-activated protein kinases extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase. These results indicate the potential of macelignan as a type I allergy treatment.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; beta-N-Acetylhexosaminidases; Calcimycin; Calcium; Cell Degranulation; Cell Line, Tumor; Cyclooxygenase 2; Dinoprostone; Extracellular Signal-Regulated MAP Kinases; Histamine Release; Hypersensitivity; Inflammation Mediators; Interleukin-13; Interleukin-4; JNK Mitogen-Activated Protein Kinases; Leukemia, Basophilic, Acute; Leukotriene C4; Lignans; Mast Cells; Myristica; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Plant Extracts; Proto-Oncogene Proteins c-akt; Rats; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Insamhodo-tang (IHT) has traditionally been used in Korea to treat a variety of diseases, including chronic cough, tuberculosis, and chronic bronchitis. However, the anti-allergic and anti-inflammatory effects of IHT and its molecular mechanisms have yet to be clearly elucidated. In this study, we attempted to evaluate the effects of IHT on mast cell-mediated allergy inflammation in vitro and in vivo.. We investigated to ascertain the pharmacological effects of IHT on both compound 48/80-induced and 2,4-dinitrofluorobenzene (DNFB)-induced allergic reactions under in vivo conditions. Additionally, to find a possible explanation for the anti-inflammatory mechanisms of IHT, we evaluated the regulatory effects of IHT on the level of inflammatory mediators in phorbol 12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cells (HMC-1).. The finding of this study demonstrated that IHT reduced compound 48/80-induced systemic anaphylactic shock, DNFB-induced dermatitis, and ear swelling responses in mice. Additionally, IHT inhibited the production of interleukin (IL)-6, IL-8, and TNF-α, as well as the activation of nuclear factor-κB and caspase-1 in PMACI-stimulated HMC-1.. Collectively, the findings of this study provide us with a novel insight into the pharmacological actions of IHT as a potential molecule for use in the treatment of allergic inflammation diseases.

Topics: Anaphylaxis; Animals; Anti-Inflammatory Agents; Calcimycin; Dermatitis; Dinitrofluorobenzene; Edema; Humans; Hypersensitivity; Inflammation; Inflammation Mediators; Ionophores; Male; Mast Cells; Medicine, Korean Traditional; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; Phytotherapy; Plant Extracts

Gomisin N is a bioactive compound and a prominent anti-allergic agent found in the fruits of tree Schizandra chinensis. However, its effects on the bone marrow-derived mast cell (BMMC)-mediated allergy and inflammation mechanism remain unknown. In this study, the biological effects of gomisin were evaluated while focusing on its effects on the allergic mediator in PMA + A23187-stimulated BMMCs. The anti-allergic effect of gomisin has shown that inhibited PMA + A23187-induced interleukin-6 (IL-6) production. An investigation was also conducted to determine its effects on the production of several allergic mediators including prostaglandin D(2) (PGD(2)), leukotriene C(4) (LTC(4)), β-hexosaminidase (β-Hex), and cyclooxygenase-2 (COX-2) protein. The results revealed that gomisin inhibited the PMA + A23187-induced production of IL-6, PGD(2), LTC(4), β-Hex, and COX-2 protein. Taken together, these findings indicate that gomisin N has the potential for use in the treatment of allergy.

Topics: Animals; Anti-Allergic Agents; Bone Marrow Cells; Calcimycin; Calcium Ionophores; Carcinogens; Cells, Cultured; Cyclooctanes; Gene Expression Regulation; Hypersensitivity; Inflammation; Inflammation Mediators; Interleukin-6; Lignans; Male; Mast Cells; Mice; Mice, Inbred BALB C; Polycyclic Compounds; Tetradecanoylphorbol Acetate

Fritillaria ussuriensis (FU, derived from the bulbs of various species of the genus Fritillaria, including Fritillaria thunbergii Miq.) is used in herbal medicine to treat conditions such as eczema, skin burns, and frostbite. In this study, we investigated the mechanism of the anti-allergy effect of FU. FU extract (80 mg/kg), orally administered to Sprague-Dawley (SD) rats, significantly inhibited the passive cutaneous anaphylaxis (PCA) reaction. It inhibited the compound 48/80-induced release of histamine from rat peritoneal mast cells in a concentration-dependent manner. Significant inhibitory effects of the FU extract on IL-6, IL-8, and TNF-α (1, 10, and 100 µg/mL) were observed in HMC-1 cells. Treatment with FU attenuated PMA plus A23187-induced phosphorylation of all three MAPKs, especially at concentrations of 10 and 100 µg/mL. Further, it (80 mg/kg) led to significant inhibition of mast-cell accumulation in ear tissue at the chronic phase. These results indicate that it inhibits allergic reactions.

Topics: Administration, Oral; Animals; Anti-Allergic Agents; Calcimycin; Fritillaria; Histamine Release; Hypersensitivity; Inflammation; Interleukin-6; Interleukin-8; Male; Mast Cells; Mitogen-Activated Protein Kinase Kinases; p-Methoxy-N-methylphenethylamine; Passive Cutaneous Anaphylaxis; Phosphorylation; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Corydalis heterocarpa is a biennial herb in South Korea, with spikes of yellow flowers. It has been used for as a folk medicine to cure travail and spasm. However, studies on this herb and its secondary metabolites have rarely been reported. In the present study, we isolated secondary metabolite libanlibanoridin from Corydalis heterocarpa. We have also examined the effect of libanoridin on the inflammatory cytokines production in phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore, A2318 stimulated human mast cell line, HMC-1. PMA plus A23187 significantly increased interleukin (IL)-1beta, IL-6, IL-8, and tumor necrosis factor (TNF)-alpha production compared to media control (P < 0.05).. We report that treatment with libanlibanoridin can inhibit PMA plus A23187-induced IL-1beta, IL-6, IL-8, and TNF-alpha production in a concentration-dependent manner with IC50 of 0.002, 1.38, 1.48, and 0.36 mug/ml, respectively. Maximal inhibition rates of IL-1beta, IL-6, IL-8, and TNF-alpha production by libanlibanoridin were about 117.5%, 86.22%, 86.41%, and 90.74%, respectively. libanoridin inhibits the mRNA expression of IL-1beta, IL-6, IL-8, and TNF-alpha. libanoridin also inhibits the expression of cyclooxygenase-2.. These results indicate that libanlibanoridin may be helpful in regulating mast cell-mediated allergic inflammatory response.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Blotting, Western; Calcimycin; Cell Culture Techniques; Cell Line; Cell Survival; Corydalis; Coumarins; Cytokines; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Humans; Hypersensitivity; Inhibitory Concentration 50; Ionophores; Mast Cells; Medicine, Korean Traditional; Reverse Transcriptase Polymerase Chain Reaction; Tetradecanoylphorbol Acetate

Andrographis paniculata has been known to possess widespread traditional application in the treatment of allergy and inflammatory diseases. In the current study, we sought to examine the effects of an extract of Andrographis paniculata leaves on inhibition of lipopolysaccharide (LPS) induced [nitric oxide (NO), prostaglandin E(2) (PGE(2)), interleukin-1beta (IL-1 beta), and interleukin-6 (IL-6)] and calcimycin (A23187) induced [leukotriene B(4) (LTB(4)), thromboxane B(2) (TXB(2)) and histamine] mediators in diverse cell based models.. Effect of an extract of Andrographis paniculata leaves (AP) was studied on inhibition of LPS induced NO, PGE(2), IL-1 beta and IL-6 in J774A.1 murine macrophages; A23187 induced LTB(4) and TXB(2) in HL-60 promyelocytic leukemic cells and histamine in RBL-2H3 rat basophilic leukemia cells.. AP illustrated significant alleviation of pro-inflammatory, inflammatory, and allergic mediators. However, no inhibition was observed against histamine release. This outcome has been summed up to deduce that AP is fairly potent in attenuating the inflammation by inhibiting pro-inflammatory (NO, IL-1 beta and IL-6), inflammatory (PGE(2) and TXB(2)) and allergic (LTB(4)) mediators.

Topics: Andrographis; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Calcimycin; Cell Line; Cell Line, Tumor; Humans; Hypersensitivity; Inflammation Mediators; Leukotriene B4; Lipopolysaccharides; Macrophages; Mice; Plant Extracts; Plant Leaves; Rats

The mast cell-mediated immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis, and sinusitis. Stimulation of mast cells starts the process of degranulation resulting in release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of aqueous extract of Teucrium japonicum Houttuyn (Labiatae) (AXTJ) on the mast cell-mediated allergy model and studied its possible mechanisms of action. AXTJ inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. AXTJ decreased immunoglobulin E-mediated passive cutaneous anaphylaxis reaction. AXTJ reduced histamine release and intracellular calcium from rat peritoneal mast cells activated by compound 48/80. In addition, AXTJ attenuated activation of nuclear factor (NF)-kappaB, and downstream tumor necrosis factor (TNF)-alpha expression in phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cells. Our findings provide evidence that AXTJ inhibits mast cell-derived allergic reactions and involvement of intracellular calcium, TNF-alpha, and NF-kappaB in these effects.

Topics: Animals; Anti-Allergic Agents; Calcimycin; Calcium; Cells, Cultured; Histamine Antagonists; Histamine Release; Hypersensitivity; Ionophores; Mast Cells; NF-kappa B; p-Methoxy-N-methylphenethylamine; Phorbol Esters; Plant Extracts; Rats; Teucrium; Tumor Necrosis Factor-alpha

The mast cell-mediated immediate-type allergic reaction is involved in many allergic diseases such as asthma, allergic rhinitis and sinusitis. Stimulation of mast cells starts the process of degranulation resulting in release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of aqueous extract of Amomum xanthiodes (Zingiberaceae) (AXE) on the mast cell-mediated allergy model and studied its possible mechanisms of action. AXE inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. AXE decreased immunoglobulin E (IgE)-mediated passive cutaneous anaphylaxis reaction. AXE reduced histamine release and intracellular calcium from rat peritoneal mast cells activated by compound 48/80. Furthermore, AXE decreased the activation of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase and c-jun N-terminal kinase, and downstream tumor necrosis factor (TNF)-alpha production in phorbol 12-myristate 13-acetate and calcium ionophore A23187-stimulated human mast cells. Our findings provide evidence that AXE inhibits mast cell-derived allergic reactions, and that intracellular calcium, TNF-alpha, and p38 MAPK are involved in these effects.

Topics: Amomum; Animals; Anti-Allergic Agents; Calcimycin; Cells, Cultured; Dose-Response Relationship, Drug; Histamine; Hypersensitivity; Male; Mast Cells; Mice; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; p38 Mitogen-Activated Protein Kinases; Phorbol Esters; Phytotherapy; Plant Extracts; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

The discovery of drugs for the treatment of allergic disease is an important subject in human health. Stimulation of mast cells starts the process of degranulation resulting in releasing of mediators, such as histamine. In this report, we investigated the effect of aqueous extract of Dracocephalum argunense Fisch. (Labiatae) (DAAE) on the mast cell-mediated allergic response and studied its possible mechanisms of action, focusing on the histamine release and pro-inflammatory cytokine secretion in mast cells. DAAE inhibited compound 48/80-induced systemic reactions and serum histamine release in mice. In addition, DAAE attenuated IgE-mediated skin allergic reaction. DAAE dose-dependently reduced IgE-induced histamine release from mast cells. The level of cAMP was transiently increased by treatment of DAAE. DAAE specifically blocked the phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187-induced p38 mitogen-activated protein kinase (MAPK) activation. DAAE decreased the secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 in mast cells. Our findings provide evidence that DAAE inhibits mast cell derived allergic reactions, and involvement of cAMP for histamine release and p38 MAPK for pro-inflammatory cytokine secretion in these effects.

Topics: Anaphylaxis; Animals; Anti-Allergic Agents; Blotting, Western; Calcimycin; Cyclic AMP; Histamine Release; Hypersensitivity; Immunoglobulin E; Interleukin-6; Lamiaceae; Male; Mast Cells; Mice; Mice, Inbred ICR; p-Methoxy-N-methylphenethylamine; p38 Mitogen-Activated Protein Kinases; Passive Cutaneous Anaphylaxis; Rats; Rats, Sprague-Dawley; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Topics: Allergens; Animals; Antibodies, Anti-Idiotypic; Basophils; Calcimycin; Cats; Drug Synergism; Hair; Histamine Release; Humans; Hypersensitivity; Mice; N-Formylmethionine Leucyl-Phenylalanine; Phthalic Acids; Time Factors

The traditional Chinese herbal formula Cang Er Zi San has been used for the treatment of rhinitis, paranasal sinusitis, and allergic rhinitis for several centuries. However, its therapeutic mechanisms remain largely unclear.. To study the effects of Shi-Bi-Lin (SBL), a modified Cang Er Zi San formula, on cytokine release from and expressions in the human mast cell line (HMC-1).. The HMC-1 was preincubated with different concentrations of SBL extract solution 1 hour before being stimulated with 25 ng/mL of phorbol myristate acetate plus 2.5 x 10(-7)M calcium ionophore A23187 and then further incubated for 6, 12, and 24 hours, respectively. The cell culture supernatants were harvested, and the cytokines of interleukin 4 (IL-4), IL-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) in the supernatants were measured by enzyme-linked immunosorbent assay. Furthermore, the total RNA of the cells was extracted, and the cytokines' messenger RNA expressions were examined using semiquantitative reverse transcriptase-polymerase chain reaction.. After different incubation periods at different concentrations, SBL could potently inhibit the cytokines of IL-4 and TNF-alpha and modestly affect IL-6 but not obviously affect IL-8 release from the HMC-1. However, no inhibitory effects were detected on the messenger RNA expressions of these cytokines.. These results demonstrate that SBL could modulate the mast cell-mediated hypersensitivity reaction in allergy. Inhibition of mast cell-derived IL-4 and TNF-alpha might explain the efficacy of SBL in treating allergic disease.

Topics: Anti-Allergic Agents; Calcimycin; Cell Line; Cytokines; Down-Regulation; Drugs, Chinese Herbal; Humans; Hypersensitivity; Interleukin-4; Ionophores; Mast Cells; RNA, Messenger; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Rat basophilic leukemia (RBL-2H3) cells are well characterized in terms of morphological and biochemical changes upon activation, and have been extensively used as a model system for studying the mechanisms of the immediate hypersensitivity reaction. To investigate whether overexpression of heat shock/stress proteins (HSP) is involved in the mast cell-dependent reactivity, we examined the adaptive responses of RBL-2H3 cells to classical stress conditions such as heat shock or oxidative injury produced by an aqueous extract of tobacco smoke.. HSP were determined by flow cytometry and immunocytochemistry. Degranulation was confirmed as the release of beta-hexosaminidase, determined spectrophotometrically, and by electron microscopy experiments.. We found that RBL-2H3 cells respond to heat shock or oxidative injury by the synthesis of both the inducible 72 kDa HSP (Hsp70), and the oxidation-specific 32 kDa heme oxygenase (HO)-1. Heat shock induced mainly Hsp70 in a cell growth-dependent manner, whereas oxidative stress induced mainly HO-1 in a cell growth-independent manner. However, heat shock or oxidative stress had no significant effects on degranulation.. Stress-mediated synthesis of HSP was not associated with RBL-2H3 degranulation and likewise, degranulation did not induce HSP.

Topics: Animals; beta-N-Acetylhexosaminidases; Calcimycin; Cell Degranulation; Cell Division; Flow Cytometry; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Hot Temperature; HSP70 Heat-Shock Proteins; Hypersensitivity; Immunohistochemistry; Ionophores; Leukemia, Basophilic, Acute; Nicotiana; Oxidative Stress; Rats; Tumor Cells, Cultured

The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) has recently been developed as a novel and cell-selective inhibitor of inflammatory cytokine secretion; it has fewer adverse effects than currently available drugs.. In this study, we investigated the capacity of pimecrolimus to directly inhibit in vitro mediator release from human skin mast cells and basophils.. Purified cutaneous mast cells or basophil-containing peripheral blood leukocytes were obtained from healthy human donors and preincubated with pimecrolimus (0.1 nmol/L to 1 micromol/L) in the absence or presence of its specific antagonist (rapamycin), cyclosporin A (100 nmol/L to 1 micromol/L), or dexamethasone (1 micromol/L) and then stimulated with anti-IgE or with calcium ionophore A23187 plus phorbol myristate acetate. Cell supernatants were kept for analysis of histamine, tryptase, LTC4, and TNF-alpha.. Pimecrolimus caused a strong and dose-dependent inhibition of anti-IgE--induced release of histamine from mast cells and basophils (maximally 73% and 82%, respectively, at 500 nmol/L pimecrolimus) and of mast cell tryptase (maximally 75%) and a less pronounced inhibition of LTC4 (maximally 32%) and of calcium ionophore plus phorbol myristate acetate--induced mast cell TNF-alpha release (90% maximum at 100 nmol/L pimecrolimus). In contrast, inhibition achieved during mast cell histamine release was maximally 60% with cyclosporin A and only 28% with dexamethasone.. These data demonstrate a marked inhibitory capacity of pimecrolimus on mediator release from human mast cells and basophils with a potency exceeding that of cyclosporin A and dexamethasone. Pimecrolimus might thus be expected to be effective in the treatment of mast cell-- and basophil-dependent diseases.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Basophils; Calcimycin; Dose-Response Relationship, Drug; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Inflammation Mediators; Mast Cells; Skin; Tacrolimus; Tetradecanoylphorbol Acetate

Misoprostol (MSP), the synthetic prostaglandin E1 (PGE1) analog, possesses multifunctional features, including modulating some inflammatory aspects of immune and allergic disorders.. To investigate the effect of MSP on histamine release (HR) from basophils of whole blood using anti-IgE, specific allergens, and calcium ionophore.. The study was performed using the automated glass fiber-based whole blood leukocyte histamine release test (LHRT).. Very low concentrations of MSP produced a marked inhibition of HR induced with anti-IgE. Maximum inhibition was observed at 10-9 M. It was also shown that the levels of HR inhibition with MSP varied at different incubation times. The greatest inhibition of HR was noted at 1 to 2 hours of incubation at MSP concentrations of 10-8 and 10-9 M, respectively. Incubation of blood from allergic patients at the optimal MSP concentration and optimal elapsed time (2 hours) resulted in significant reductions of allergen-specific HR induced by both Timothy pollen grass allergen and D.pteronissinus. Incubation of blood with varying concentrations of MSP and subsequent stimulation with calcium ionophore A23187 also inhibited HR from basophils. In the latter case, the most effective concentrations of MSP ranged from 10-8 to 10-6 M.. This study demonstrated that MSP can inhibit basophil HR indicating a potentially beneficial role of PGE1 analogs as pharmacotherapy for allergic diseases.

Topics: Anti-Ulcer Agents; Antibodies, Anti-Idiotypic; Basophils; Binding Sites, Antibody; Calcimycin; Histamine Release; Humans; Hypersensitivity; Ionophores; Misoprostol; Oxytocics

The release of histamine and leukotriene C4 (LTC4) from bronchoalveolar lavage (BAL) cells and peripheral blood stimulated with Ca ionophore A23187 was compared between atopic and nonatopic asthma. The proportion of basophilic cells in BAL fluid was significantly higher in atopic than in nonatopic asthma (p < 0.01); however, no significant differences were present in the other BAL cells between the two asthma types. The concentration of histamine in BAL fluid was significantly higher in younger patients (20-59 years) with atopic than in nonatopic asthma (p < 0.01). In contrast, the concentration of LTC4 was significantly higher in nonatopic than in younger patients with atopic asthma (p < 0.01). The release of histamine from BAL cells (p < 0.001) and peripheral blood (p < 0.01) was significantly larger in younger patients with atopic than in nonatopic asthma. The generation of LTC4 by BAL cells was significantly larger in nonatopic than in younger (p < 0.01) and older patients with atopic asthma (60+ years) (p < 0.05). These results suggest that both histamine and LTC4 participate in the onset mechanism of atopic asthma, and only LTC4 participates in that of nonatopic asthma.

Topics: Adult; Aging; Asthma; Blood Cells; Bronchi; Bronchoalveolar Lavage Fluid; Calcimycin; Female; Histamine; Humans; Hypersensitivity; Ionophores; Leukotriene C4; Male; Middle Aged; Pulmonary Alveoli

Rat peritoneal mast cells are stimulated to generate superoxide anion (O2) by the addition of compound 48/80 and A23187. Recently, we demonstrated by immunohistochemical and Western blot analysis that the mast cells contained the p47phox protein, which was one of cytosolic component of the NADPH oxidase system. In the present study, it was demonstrated that the mast cells contained the p47phox mRNA, much similar to that of mouse leukocyte. The permeabilized mast cells were stimulated to generate O2- by the addition of Ca2+, phospholipase A2 (PLA2) and arachidonic acid. Our data suggest the following:(1) cytosolic PLA2 may be activated by the elevation of [Ca2+]i; (2) the conjugation of membrane component with cytosolic component may be stimulated by the released arachidonic acid. The mast cell granules contained superoxide dismutase (SOD)-like enzyme, which degradated O2-, generated in xanthine-xanthinoxidase system. SOD-like enzyme was released from the granules by the treatment with Ca2+ and trapped by the treatment with heparin. In conclusion, our studies suggest that the disorder of the degradation system of O2- may contribute to the development of allergic inflammation.

Topics: Animals; Ascitic Fluid; Calcimycin; Hypersensitivity; Inflammation; Male; Mast Cells; NADPH Oxidases; p-Methoxy-N-methylphenethylamine; Phosphoproteins; Rats; Rats, Wistar; Superoxide Dismutase; Superoxides

Tobacco smoking induces an increased nonspecific IgE response. IgE synthesis is controlled by IL-4 and IFN-gamma. The effect of nicotine (10(-10) to 10(-5) M), one of the major components of tobacco smoke, were studied on IL-4 and IFN-gamma release by peripheral blood mononuclear cells from 12 allergic patients and 12 nonallergic subjects and 16 T cell clones stimulated by nonspecific agonists (phorbol myristate acetate and calcium ionophore). The release of IL-4 and IFN-gamma was measured by ELISA in supernatants after a 48-hour culture. Nicotine did not modify IL-4 and IFN-gamma release by peripheral blood mononuclear cells or T cell clones. The effects of tobacco smoke on IgE production are unlikely to change in the T cell phenotype by nicotine.

Topics: Calcimycin; Carcinogens; Clone Cells; Enzyme-Linked Immunosorbent Assay; Humans; Hypersensitivity; Immunoglobulin E; Immunophenotyping; Interferon-gamma; Interleukin-4; Ionophores; Leukocytes, Mononuclear; Lymphocyte Activation; Nicotine; T-Lymphocytes; Tetradecanoylphorbol Acetate

The effects of three histamine H1 receptor antagonists, epinastine (CAS 80012-43-7, WAL-801 CL), ketotifen (CAS 34580-13-7) and oxatomide (CAS 60607-34-3), on mediator release have been studied in human peripheral leukocytes. When leukocytes from asthmatic patients sensitive to mite were stimulated with the allergen, epinastine inhibited histamine release with a concentration required for 50% inhibition (IC50) of 3 x 10(-5) mol/l and leukotriene C4 generation. On the other hand, ketotifen or oxatomide showed little inhibiting effect on histamine release elicited with the allergen. When the cells were stimulated with calcium ionophore A23187, epinastine failed to inhibit histamine release and leukotriene C4 generation. Oxatomide caused a concentration related inhibition of calcium ionophore-induced histamine release with the IC50 value of 5 x 10(-5) mol/l. Ketotifen or oxatomide also showed an inhibition of leukotriene C4 generation induced by calcium ionophore in a dose-dependent manner and the IC50 value was 6 x 10(-6) mol/l for oxatomide and 8 x 10(-5) mol/l for ketotifen, suggesting that oxatomide is a more potent inhibitor of leukotriene C4 generation than ketotifen. These results indicate that epinastine inhibits IgE-mediated histamine release and LTC4 generation, and oxatomide has a capacity to inhibit calcium ionophore-induced mediator release from human leukocytes. Additionally, when platelet activating factor was quantitated by radioimmunoassay in the supernatant and the cell pellet after ionophore stimulation, epinastine inhibited the formation and the secretion in a dose-dependent manner.

Topics: Asthma; Calcimycin; Dibenzazepines; Histamine H1 Antagonists; Humans; Hypersensitivity; Imidazoles; Immunoglobulin E; In Vitro Techniques; Ketotifen; Leukocytes; Leukotriene C4; Neutrophils; Piperazines; Platelet Activating Factor

The inhibitory effects of alkylphenyl alpha-D-mannopyranosides on histamine release from rat peritoneal mast cells induced by an antigen-antibody reaction were examined. Among the compounds tested, 2,4,6-trimethylphenyl alpha-D-mannopyranoside exhibited the strongest inhibitory effect. Furthermore, the 2,4,6-trimethylphenyl alpha-D-mannopyranoside suppressed the Schultz-Dale reaction and 48 h homologous passive cutaneous anaphylaxis (PCA), suggesting that this compound may be a useful lead compound in the development of novel anti-allergy drugs.

Topics: Animals; Calcimycin; Histamine Release; Hypersensitivity; Male; Mannosides; Mast Cells; Passive Cutaneous Anaphylaxis; Peritoneum; Rats; Rats, Wistar; Structure-Activity Relationship

IL-4 protein and mRNA have recently been detected in pure basophil cultures after stimulation. It has also been established in mixed leukocyte cultures obtained by elutriation and challenged with anti-IgE that the basophil is the only cell that makes detectable IL-4. We have used cells prepared using Percoll gradients (5 to 30% basophils) to study the relationship between histamine release and IL-4 synthesis. In cultures challenged with anti-IgE after a 15-min pretreatment with IL-3, detectable IL-4 secretion ranged from 40 to 630 pg/10(6) basophils in 18 of 22 donors, with no significant correlation (r = 0.21, p = 0.34) with basophil purity. IL-4 synthesis was dissociated from histamine release, with optimal production consistently occurring at 10 ng/ml anti-IgE, whereas histamine levels peaked at 50 to 100 ng/ml of stimulus. Stimulation with anti-IgE alone was sufficient for IL-4 secretion but protein levels were enhanced two- to threefold in low responders by increasing the calcium concentration to 5 mM with no significant changes in histamine release. The IgE-independent secretagogues, F-met peptide (1 microM) and C5a (25 ng/ml), demonstrated limited ability to generate detectable IL-4, despite promoting vigorous histamine release. Additional studies showed no significant difference between IL-4 secretion in atopic and nonatopic donors. Finally, IL-4 levels generated with specific Ags were comparable to those levels produced in response to anti-IgE. We predict that basophil IL-4 generation will have a proinflammatory effect, but it appears that the signal transduction mechanisms for its synthesis and release differ from those for histamine release and thus may require different methods of pharmacologic control.

Topics: Basophils; Calcimycin; Cells, Cultured; Complement C5a; Cytokines; Dose-Response Relationship, Immunologic; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; In Vitro Techniques; Interleukin-3; Interleukin-4; N-Formylmethionine Leucyl-Phenylalanine

The inhibitory effects of azelastine hydrochloride on PAF-induced and fMLP-induced Ca2+ influx, actin polymerization and calcium ionophore A23187-induced and aggregated IgG-induced release of eosinophil cationic protein (ECP) of an eosinophilic leukaemia cell line, EoL-1, were examined. EoL-1 cells cultured with 0.2 mM dibutyryladenosine-cyclic monophosphate for 48 hours showed an increase in intracellular free Ca2+ concentration ([Ca2+]i) and actin polymerization when stimulated by PAF and fMLP. Azelastine hydrochloride inhibited PAF-induced and fMLP-induced Ca2+ influx ([Ca2+]i) in a dose-dependent manner with an IC50 of 1 x 10(-8) M and 1 x 10(-7) M, respectively. It also inhibited PAF-induced and fMLP-induced actin polymerization in a dose-dependent manner up to 40% and 30%, respectively. EoL-1 cells were differentiated to contain ECP in their eosinophilic granules when cultured for 9 days with supernatants of a human adult T cell leukaemia cell line, HIL-3 (HIL-3 sup). Calcium ionophore A23187 and aggregated IgG induced the secretion of ECP by EoL-1 cells. Azelastine hydrochloride inhibited the secretion of ECP in a dose-dependent manner. These inhibitory effects were seen even at therapeutic concentrations of 10(-8) M to 10(-9) M. These results indicate that the therapeutic effects of azelastine hydrochloride as an anti-allergic agent may include inhibition of the accumulation of eosinophils into the locus of allergic inflammation and of the release of cytotoxic granules from eosinophils.

Topics: Actins; Blood Proteins; Bucladesine; Calcimycin; Calcium-Transporting ATPases; Cell Differentiation; Culture Media; Dose-Response Relationship, Drug; Eosinophil Granule Proteins; Eosinophils; Humans; Hypersensitivity; Immunoglobulin G; Inflammation; Leukemia, Eosinophilic, Acute; Leukemia, T-Cell; Lipoxygenase Inhibitors; N-Formylmethionine Leucyl-Phenylalanine; Phthalazines; Platelet Activating Factor; Polymers; Ribonucleases; Tumor Cells, Cultured

The effect of disodium cromoglycate on in vitro proliferative responses of peripheral blood mononuclear cells from healthy individuals, allergic patients with moderate serum IgE and patients with atopic dermatitis and high levels of serum IgE was investigated. Peripheral blood mononuclear cells were stimulated with mitogens (phytohaemagglutinin, Concanavalin A), recombinant interleukin-2, calcium ionophore + phorbol 12-myristate 13-acetate, purified protein derivative of tuberculin and allergens. It was possible to induce in vitro specific, allergen-triggered responses only in allergic individuals with moderate serum IgE and not in individuals with atopic dermatitis and high serum IgE. Generally, whenever the stimulatory signal(s) caused a significant proliferative response, disodium cromoglycate inhibited the proliferation. This inhibition was seen for all activation agents and for both healthy and allergic individuals. By contrast, for certain non- or low-responders (both healthy and allergic individuals) disodium cromoglycate seemed to amplify the proliferation to various activation signals. Only non- or low-responder cells derived from atopic dermatitis patients showed a biphasic kinetic response pattern when stimulated with the drug in combination with recombinant interleukin-2, recombinant interleukin-2 + ionophore or specific allergens.

Topics: Calcimycin; Cells, Cultured; Cromolyn Sodium; Dermatitis, Atopic; Female; Humans; Hypersensitivity; Interleukin-2; Lymphocyte Activation; Male; Recombinant Proteins; Tuberculin

1. We have investigated the capacities of peripheral leukocytes from atopic asthmatic (AA) (n = 7), atopic non-asthmatic (AN) (n = 7), and normal (N) (n = 7) subjects to generate the bronchoconstrictor and proinflammatory mediators leukotrienes (LTs) B4 and C4. 2. Mixed leukocyte preparations containing 61-84% neutrophils, 2.4-15% eosinophils, and 13-29% mononuclear cells were incubated in vitro at 37 degrees C in the presence of calcium ionophore A23187. Synthesis of LTB4 and LTC4 was quantitated by radioimmunoassay. 3. Both in dose-response experiments (0-10 microM A23187 for 5 min), and in time-course investigations (2 microM A23187 for 0-30 min), the mixed leukocytes of the AA and AN subjects generated on average 4- to 5-fold more LTB4 and 3- to 5-fold more LTC4 than the normal leukocytes (P less than 0.01 in all cases; ANOVA). 4. This enhanced LT synthesis by the AN and AA leukocytes was not due to differences in the counts of leukocyte sub-types, or to altered rates of LT catabolism between the subject groups. 5. LTB4 synthesis correlated significantly with LTC4 synthesis in the leukocytes of the AN and AA subjects (r = 0.81, n = 14, P less than 0.01), but not in those of the normal subjects (r = 0.19, n = 7, P greater than 0.05). 6. Our results demonstrate an up-regulation of the leukotriene synthetic pathway in the circulating leukocytes of atopic non-asthmatic and atopic asthmatic subjects, which may have important implications in the pathophysiology of asthma and allergy.

Topics: Adolescent; Adult; Asthma; Calcimycin; Cells, Cultured; Dose-Response Relationship, Drug; Female; Humans; Hypersensitivity; Leukocytes; Leukotrienes; Male; Middle Aged

The histamine release (HR) after challenge with anti-IgE, concanavalin A, N-formyl-met-leu-phe and the calcium ionophore A23187 from 97 cord blood samples was determined by a microfiber-based assay. Maximum HR with anti-IgE showed great inter-individual variation (median: 20.5; range: 1-104 ng/ml blood), but was not significantly different from the results obtained in identically treated blood samples from 50 adults (median: 23; range: 1-93 ng/ml blood). Both the maximum HR and the sensitivity to anti-IgE were dependent on total plasma IgE content. Blood samples with plasma IgE greater than or equal to 0.5 IU/ml (n = 15) had significantly higher maximum HR than those with plasma IgE less than 0.5 IU/ml (n = 82; median: 32 vs. 18 ng/ml blood; p less than 0.01). Passive sensitization with IgE-rich atopic plasma increased the maximum HR with anti-IgE only in samples with a plasma IgE content of less than 0.5 IU/ml, although sensitivity to anti-IgE was universally increased. Preincubation with pharmacologic agents modulating the IgE-mediated HR produced effects generally similar to previous findings in adult blood. However, the effects of inhibiting the cyclooxygenase pathway in cord blood differed from our observations in adult blood, and may represent a maturational phenomenon. The family history of allergy was obtained by a questionnaire, and clinical observations were gathered from patient records. None of these parameters were found to influence HR with any secretagogue. However, HR stimulated by the calcium ionophore A 23187 was found to be highly dependent on the storage time of the EDTA-anticoagulated blood samples, which should be carefully controlled.

Topics: Basophils; Blood Preservation; Calcimycin; Concanavalin A; Female; Fetal Blood; Fluorometry; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Male; N-Formylmethionine Leucyl-Phenylalanine; Pregnancy; Surveys and Questionnaires

We tested the hypothesis that allergic sheep that develop both early and late airway responses to inhaled Ascaris suum antigen (late responders) have an increased capacity to generate leukotrienes (LTs) compared with allergic sheep that show only early responses to inhaled antigen (acute responders). To test this hypothesis, we measured LTB4 production, in vitro, by granulocytes isolated from peripheral blood and by macrophages isolated from bronchoalveolar lavage (BAL) from both groups of sheep greater than or equal to 2 wk after the animal's last antigen challenge; LTB4 production by granulocytes isolated from BAL from both groups of sheep 6 and 48 h after local airway challenge with A. suum antigen was also measured. LTB4 production was induced by incubating cells (i.e., either granulocytes or macrophages) with calcium ionophore (A23187, 2 microM) and arachidonic acid (30 microM). LTB4 production was quantitated by high-performance liquid chromatography and verified by radioimmunoassay (RIA). On stimulation peripheral blood granulocytes from late responders (n = 7) produced (means +/- SD/10(6) cells) 13.3 +/- 5.2 ng LTB4 compared with 5.3 +/- 1.5 ng LTB4 (P less than 0.05) for acute responders (n = 7). This increased LTB4 production did not result from variations in granulocyte differential or cyclooxygenase activity (as indicated by RIA measurements of prostaglandin E2 production).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens, Helminth; Arachidonic Acid; Arachidonic Acids; Ascaris; Calcimycin; Cell Adhesion; Granulocytes; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Lung; Macrophages; Reference Values; Sheep; Therapeutic Irrigation

1. Inflammatory cells such as eosinophils and neutrophils are thought to contribute actively to the pathogenesis of asthma by the release of bronchoconstrictor mediators including leukotrienes. Previous studies have revealed the almost exclusive synthesis of leukotriene C4 (LTC4) by human eosinophils and of leukotriene B4 (LTB4), 20-OH-LTB4 and the non-enzymatically formed LTB4-isomers by neutrophils when stimulated in vitro with the calcium ionophore A23187 or opsonized zymosan (OZ). In this study we have investigated whether nedocromil sodium, a new anti-asthma drug, was capable of inhibiting A23187- and OZ-induced leukotriene formation by these cells. 2. Nedocromil sodium inhibited A23187- and OZ-induced LTC4 formation by eosinophils in a concentration-dependent manner (mean IC30 for A23187: 5.6 X 10(-5) M; mean IC30 for OZ: 6.3 X 10(-5) M), whereas it did not inhibit A23187- and OZ-induced LTB4 formation by neutrophils. 3. Extension of the preincubation time of the cells with the drug did not alter the observed inhibitory capacity. The optimal preincubation time was 5 min. 4. The in vitro inhibition of LTC4 formation by eosinophils by nedocromil sodium may be a valuable property of this drug in the treatment of asthma.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Asthma; Calcimycin; Eosinophils; Humans; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Nedocromil; Neutrophils; Quinolones; Zymosan

The effects of 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA-861), a selective 5-lipoxygenase inhibitor, on immunological or non-immunological release of slow reacting substance of anaphylaxis (SRS-A) and histamine and its effects on experimental asthma were investigated. AA-861 showed a dose-dependent inhibition of SRS-A release, with no effect on histamine release from passively sensitized guinea pig, monkey (M. irus) and human lung fragments. An analysis of the anaphylactic diffusate from the human lung fragments, using the combined technique of high performance liquid chromatography and radioimmunoassay, revealed that AA-861 markedly suppresses biosynthesis of the leukotrienes. However, this drug inhibits the release of histamine as well as SRS-A from lung fragments of anaphylactic monkey (M. mulatta) and in the Ca ionophore-stimulated rat peritoneal cavity. AA-861 suppressed the anaphylactically-induced airway resistance in mepyramine- and cimetidine-treated guinea pigs. These results suggest that AA-861 may be clinically effective for treating allergy-related asthma by modulating the 5-lipoxygenase pathway and that an inhibitory mechanism of histamine release by AA-861 may be present in some species.

Topics: Animals; Asthma; Benzoquinones; Calcimycin; Chromatography, High Pressure Liquid; Female; Guinea Pigs; Histamine; Histamine Release; Hypersensitivity; Lipoxygenase Inhibitors; Macaca; Macaca mulatta; Male; Mites; Quinones; Radioimmunoassay; Rats; Rats, Inbred Strains; Species Specificity; SRS-A

Activated neutrophils may play a part in atopic disorders. In these studies, neutrophils were obtained from atopic and nonatopic adults for assessment of respiratory-burst activity. Superoxide production was measured in the resting state and after stimulation with phorbol myristate acetate, formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe), or calcium ionophore A23187. Inhibition of this response by histamine was also measured. Neutrophils from atopic subjects produced more superoxide in the basal state, or in response to calcium ionophore A23187, or submaximal concentrations of f-met-leu-phe, than cells from control subjects. Histamine inhibition of f-met-leu-phe-stimulated superoxide production was less in atopic subjects than in control subjects. These findings suggest that neutrophils from atopic subjects may be hyperreactive in that they produce more superoxide in response to stimuli of low potency and are less readily inhibited than cells from control subjects. These properties may reflect a general attribute of cellular function in atopy and may contribute directly to tissue damage in allergic diseases.

Topics: Calcimycin; Histamine; Humans; Hypersensitivity; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxygen Consumption; Superoxides; Tetradecanoylphorbol Acetate

The ability of selected lipoxygenase inhibitors (LI) to influence allergic and nonallergic histamine secretion was studied. LI were found to exert concentration-dependent inhibition of allergic histamine release from rat peritoneal mast cells (RPMC) with the following IC50s, microM: nordihydroguaiaretic acid (NDGA) = 3.9; 5, 8, 11, 14-eicosatetraynoic acid (ETYA) = 3.8 and BW 755c = greater than 10. Calcium ionophore A23187 (0.2 microM)-induced histamine release from RPMC was also inhibited by these agents in a concentration-dependent fashion. The IC50s, microM were as follows: NDGA = 1.9; ETYA = 5.9 and BW 755c = greater than 10. Allergic histamine release from rabbit mixed leukocytes was inhibited by these drugs. The IC50s, microM, were as follows: NDGA = 1.4; BW 755c = 1.9 and ETYA = 7.2. These data suggest that the products of 5-lipoxygenase(s), e.g., 5-HPETE, 5-HETE, etc., may modulate (regulate) histamine secretion process(es).

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; 5,8,11,14-Eicosatetraynoic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcimycin; Catechols; Fatty Acids, Unsaturated; Histamine Release; Hypersensitivity; Kinetics; Lipoxygenase Inhibitors; Masoprocol; Mast Cells; Pyrazoles; Rabbits; Rats; Rats, Inbred Strains

Topics: Age Factors; Animals; Antibodies, Anti-Idiotypic; Asthma; Basophils; Calcimycin; Dermatitis, Atopic; Deuterium; Deuterium Oxide; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; N-Formylmethionine Leucyl-Phenylalanine; Phenotype; Water

The effects of 11-oxo-11H-pyrido[2,1-b]-quinazoline-2-carboxylic acid (Sm 857), a new antiallergic drug, on histamine release from human leukocytes and from human and monkey lungs were investigated. Sm 857 dose-dependently inhibited histamine release induced by mite antigen, anti-human IgE, calcium ionophore A23187 (A23187) and protein A from peripheral leukocytes of atopic patients, but had no effect on the levels of cyclic AMP and GMP in human leukocytes. In addition, antigen- or anti-human IgE-induced anaphylactic histamine release from human and monkey lung fragments passively sensitized with human reaginic serum sensitive to mite antigen as well as A23187-induced histamine release from non-sensitized monkey lung fragments, were inhibited dose-dependently by Sm 857. However, no inhibition of spontaneous histamine release from human leukocytes or monkey lung fragments by Sm 857 was observed.

Topics: Animals; Calcimycin; Cyclic AMP; Cyclic GMP; Histamine Release; Humans; Hypersensitivity; Leukocytes; Lung; Macaca; Mites; Quinazolines

Amoxanox has potent antiallergic activity because it inhibits the release of chemical mediators such as histamine and leukotrienes. We studied the in vitro effect of amoxanox on arachidonic acid metabolism, including the lipoxygenase and cyclooxygenase pathways. Amoxanox inhibited calcium ionophore A23187-induced formation of 5-HETE, LTB4, SRS-A (LTC4, LTD4 and LTE4), and 12-HETE in rat peritoneal resident monocytes. These results indicate that amoxanox inhibits 5- and 12-lipoxygenases. The compound, however, did not affect the formation of TXB2 or 6-keto-PGF1 alpha in guinea pig lung fragments and PGE2 or PGF2 alpha in bovine seminal vesicles, suggesting that it did not inhibit cyclooxygenase. These results show that the antiallergic action of amoxanox is associated, at least in part, with the reduction of leukotrienes due to the inhibition of lipoxygenases.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 5,8,11,14-Eicosatetraynoic Acid; Aminopyridines; Animals; Asthma; Calcimycin; Cattle; Guinea Pigs; Histamine H1 Antagonists; Hydroxyeicosatetraenoic Acids; Hypersensitivity; In Vitro Techniques; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Male; Monocytes; Prostaglandins; Rats; Rats, Inbred Strains; SRS-A; Thromboxane B2

Preincubation of peripheral leukocytes from atopics and normals significantly enhanced histamine release induced by anti-IgE and calcium ionophore. On the other hand, there was a significant inhibition (ca. 40%) of C5a-induced histamine release by indomethacin both in atopics and controls. In the group of patients with atopic eczema, anti-IgE-induced histamine release was significantly higher than in controls both without and with indomethacin.

Topics: Adolescent; Adult; Antibodies, Anti-Idiotypic; Basophils; Calcimycin; Complement C5; Complement C5a; Dinoprostone; Eczema; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Indomethacin; Middle Aged; Prostaglandins E

RHC 3164 has been investigated for its antiallergic activities in 3 in vitro models of anaphylaxis. RHC 3164 was 6 times more potent than DSCG as an inhibitor of antigen-induced release of histamine (AIR) from rat mast cells (RMC) and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties, cross-tachyphylaxis to DSCG, and inability to inhibit nonimmunologic release of histamine. Neither RHC 3164 nor DSCG had any effect on immunologic release of histamine from human basophils or guinea pig lung slices. We conclude that RHC 3164 is a potent inhibitor of immunologic release of histamine from RMC with a mechanism of action similar to that of DSCG.

Topics: Animals; Basophils; Calcimycin; Cromolyn Sodium; Dextrans; Dose-Response Relationship, Drug; Guinea Pigs; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity; Lung; Mast Cells; Phosphatidylserines; Rats; Tachyphylaxis; Time Factors; Triazoles

Topics: Animals; Antigen-Antibody Complex; Autacoids; Calcimycin; Hypersensitivity; Immunoglobulin E; Lung; Macrophages; Male; Pulmonary Alveoli; Rats; Secretory Rate; SRS-A

Cord basophil preparations from 53 term neonates were studied for various factors affecting immediate hypersensitivity reactions including: basophil IgE receptor density and histamine releasability following incubation with calcium ionophore A23187, zymosan-activated serum (C5a), and anti-IgE. Basophil histamine content (geometric mean, 0.4 pg/basophil, with content in 14/28 cord blood samples below 0.2 pg/cell) is considerably below that of atopic and nonatopic individuals (geometric mean, 2.3 pg/basophil). Histamine release is normal with both A23187 (range 33% to 88%) and C5a (range 11% to 58%). Normal release with anti-IgE was shown in five of nine cord blood samples (range 13% of 52%), but four of five cell preparations required IgE preincubation. Indirect evidence indicates that basophils from newborns contain less than 30,000 total IgE receptors/cell. IgE-mediated histamine release in basophils from newborns is minimized by suboptimal IgE binding. Optimal IgE binding is not favored in basophils from neonates because of low serum IgE and low IgE receptor density. Serum IgE and IgE receptors increase to a variable degree as the child grows older and may determine the clinical onset of allergic disease.

Topics: Adult; Basophils; Calcimycin; Complement C5; Complement C5a; Fetal Blood; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Infant, Newborn; Receptors, Immunologic

A dual isolated organ technique comprised of a guinea-pig lung parenchymal strip and a guinea-pig ileum was used to determine if slow reacting substance of anaphylaxis (SRS-A) is released from parenchyma during contractions evoked by antigen (ovalbumin) or by ionophore (A23187). An immunologically sensitized parenchyma served as the primary target organ for ovalbumin and either a sensitized or unsensitized parenchyma was the target tissue for A23187; an unsensitized ileum functioned as the assay organ. In the presence of pyrilamine and indomethacin, ovalbumin or A23187 produced contractions of the parenchyma and concomitantly caused release of SRS-A from the lung strip which was indicated by a contraction of the ileum. The ileal response was antagonized by FPL 55712, whereas the parenchyma contractions were unaffected. Additional experiments were conducted in which parenchyma was contracted with histamine. At the height of the histamine contraction, the bathing fluid surrounding the parenchyma was removed and assayed on a pyrilamine-treated ileum. SRS-A was not detected, indicating that SRS-A release from parenchyma is not a function of tissue contraction per se, but is related to the antigen- and ionophore-induced contractions. To explain the lack of effect of FPL 55712 on parenchymal contractions to antigen or ionophore, we compared the degree of antagonism produced by FPL 55712 on SRS-A contraction of parenchyma and ileum. These experiments indicated the possibility that at least two different classes of SRS-A receptors exist and that those in the ileum and lung differ.

Topics: Animals; Calcimycin; Chromones; Guinea Pigs; Histamine; Hypersensitivity; In Vitro Techniques; Lung; Male; Muscle Contraction; Muscle, Smooth; Ovalbumin; SRS-A; Time Factors

Topics: Animals; Anti-Bacterial Agents; Ascitic Fluid; Calcimycin; Cromolyn Sodium; Cyclic AMP; Female; Histamine Release; Hypersensitivity; In Vitro Techniques; Male; Mast Cells; Rats; Theophylline; Time Factors

Topics: Anaphylatoxins; Animals; Calcimycin; Cytoplasmic Granules; Cytotoxicity, Immunologic; Guinea Pigs; Humans; Hypersensitivity; Immunoglobulin E; Mast Cells

Three new antiallergic drugs, Doxantrazole, PRD-92 and N5', as well as disodium cromoglycate, inhibited the IgE-mediated PCA reaction in the rat triggered by the homologous antigen, but did not have an antagonistic effect on histamine itself. Moreover, all the drugs examined caused in vitro inhibition of antigen-mediated histamine release from peritoneal mast cells and chopped lung tissue of sensitized rats producing IgE antibodies. Doxantrazole had a synergistic effect on the inhibition of histamine release by isoproterenol, whereas the other drugs were devoid of this capacity. PRD-92 and N5' inhibited the ionophore A23,187 induced histamine release, but did not have any effect on the D2O-enhanced histamine release which was triggered by antigen.

Topics: Animals; Antigens; Calcimycin; Capillary Permeability; Cromolyn Sodium; Deuterium; Diphenhydramine; Drug Synergism; Female; Histamine Release; Hypersensitivity; Lung; Mast Cells; Passive Cutaneous Anaphylaxis; Rats

Topics: Animals; Antigen-Antibody Reactions; Binding, Competitive; Bucladesine; Burimamide; Calcimycin; Calcium; Cholera; Cyclic AMP; Enterotoxins; Epinephrine; Histamine; Histamine H1 Antagonists; Histamine Release; Humans; Hypersensitivity; Immunoglobulin E; Isoproterenol; Leukocytes; Mast Cells; Metiamide; Prostaglandin Antagonists; Rats