Bronchial asthma: the possible role of the chemical mediators of immediate hypersensitivity in the pathogenesis of subacute chronic disease.
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Acetylcholine↗
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Airway sensitivity to slow-reacting substance of anaphylaxis, histamine, and antigen in Ascaris sensitive monkeys.
The effects of Ascaris suum antigen, histamine, and slow-reacting substance of anaphylaxis (SRS-A) on the respiratory system were compared in 3 anesthetized rhesus monkeys. The agents were administered by instillation into the trachea, and the animals were studied in a volume displacement body plethysmograph. Two of the animals showed skin and bronchial sensitivity to Ascaris suum antigen and responded to it with increased pulmonary resistance and decreased dynamic compliance. A similar response was seen in all 3 animals after instillation of histamine, but SRS-A at 2 concentrations produced a predominant effect of decreased dynamic compliance with lesser alterations in pulmonary resistance. The effects of SRS-A were slow in onset and prolonged, as compared to the abrupt and short-lived effects of Ascaris suum antigen and histamine. The predominant effect of SRS-A on dynamic compliance suggests a more peripheral site of action of this mediator. In 5 monkeys allergic to Ascaris, no SRS-A could be detected in the blood at one and 5 min after antigen challenge, using the bioassay techniques.
Administration, Topical↗
Recombinant stem cell factor-induced mast cell activation and smooth muscle contraction in human bronchi.
The effect of human recombinant stem cell factor (SCF) on inflammatory mediator release and smooth muscle contraction was evaluated in human isolated intralobar bronchi. Bronchi from 21 of 26 donors contracted in response to SCF. The threshold concentration was approximately 0.01 micrograms/ml. At 1 micrograms/ml, the tissues contracted to about 60% of the carbamylcholine-induced maximum contraction. The responses to SCF mimicked those obtained with anti-IgE. Thus, the contractions to SCF and anti-IgE were inhibited to a similar extent by a combination of a cysteinyl-leukotriene receptor antagonist and a histamine H1 receptor antagonist. SCF also mimicked the effect of anti-IgE in releasing histamine, i-LTD4, and PGD2 from the bronchi. At a threshold concentration for contraction (0.01 micrograms/ml), SCF had no effect on subsequent responses to anti-IgE in the bronchi. The data suggest that human recombinant SCF contracts airway smooth muscle by stimulating the release of contractile mediators from bronchial mast cells. The data fail to support the hypothesis that SCF primes bronchial mast cells to subsequent immunologic stimuli.
Antibodies, Anti-Idiotypic↗
Release of a slow-reacting substance from rabbit platelets.
Washed rabbit platelets stimulated with platelet-activating factor, thrombin, or arachidonic acid, released a slow-reacting substance (SRS), whereas platelets aggregated by adenosine diphosphate did not. Production of platelet-derived SRS was neither affected by indomethacin nor aspirin but was reduced by large doses of eicosatetraynoic acid, an inhibitor of the cyclo-oxygenase and lipoxygenase. L-cysteine enhanced markedly the release of SRS from platelets. This SRS activity, which was antagonized by FPL 55712 and inactivated by arylsulfatase, followed the same elution pattern on Amberlite, silicic acid, and reverse phase high-pressure liquid chromatography columns as that described for the SRS from other origins. SRS activity released from platelets preincubated with [14C]arachidonic acid exhibited the same retention time as radioactivity in reverse phase high-pressure liquid chromatography. The release of a SRS from platelets is consistent with their implication in the pathogenesis of asthma and other lung diseases.
5,8,11,14-Eicosatetraynoic Acid↗
Effects of dexamethasone on mediator release from human lung fragments and purified human lung mast cells.
Purified human lung mast cells released histamine, leukotrienes, prostaglandin (PG) D2, thromboxane B2 (TxB2), and PGF2 alpha in response to anti-IgE stimulation. Incubation of the cells for 24 h with 10(-6) M dexamethasone, a treatment that inhibits mediator release from human basophils, had no effect on the release of these mediators from mast cells. Dexamethasone treatment of human lung fragments led to little or no inhibition of anti-IgE-induced release of the mast cell-derived mediator, histamine, but produced a significant inhibition of the release of PGE2, PGF2 alpha, and 6-keto-PGF1 alpha. As was the case with purified mast cells, the steroid did not inhibit the release of PGD2 or TxB2 from human lung fragments. Comparison of the quantities of PGD2 and TxB2 produced by purified cells and human lung fragments reveals that the mast cells produce quantities of these metabolites sufficient to account for the entire amount produced by challenged lung fragments. Dexamethasone inhibited spontaneous release from lung fragments of all cyclooxygenase products measured. These results suggest that the human lung parenchymal mast cell phospholipase is not inhibited by dexamethasone, whereas other phospholipase(s) in the lung are inhibited by the steroid. These results may be useful in explaining the resistance of acute allergic reactions, including anaphylaxis, to steroids, despite the potent antiinflammatory activity of steroids on subacute and chronic inflammation, such as in bronchial asthma, which may be initiated by IgE-dependent mechanisms.
Autacoids↗
Rat model of platelet-activating factor-induced rhinosinusitis.
Platelet-activating factor (PAF) is known to be a potent inflammatory mediator, especially in allergic inflammation. However, the exact role of PAF in the pathogenesis of rhinosinusitis has not been clearly established. To understand the role of PAF in the pathogenesis of rhinosinusitis, it is necessary to develop an animal model of PAF-induced rhinosinusitis. The aim of this study was to develop a rat model of rhinosinusitis induced by intranasally applied PAF. Fifty microliters of 16 microg/mL PAF was applied intranasally through each naris in 4-week-old Sprague-Dawley rats, and the same amount of vehicle was applied in control rats. At 1, 3, or 5 days, the animals were painlessly sacrificed, and the nasal cavity and sinuses were prepared for histologic investigation. The histologic sections were examined in a blind manner for the appearance of neutrophil clusters in the sinonasal air space, and the numbers of eosinophils, areas of epithelial loss, goblet cells, and inducible nitric oxide synthase (iNOS)-positive inflammatory cells in the mucosa. Neutrophil clusters were observed in the air space, and the number of eosinophils, areas of epithelial loss, goblet cells, and iNOS-positive inflammatory cells in the mucosa were increased significantly in the PAF-applied rats. The amount of inflammation varied according to the time interval, showing a peak at day 3. We conclude that intranasally applied PAF induces rhinosinusitis in rats. The histologic evidence of rhinosinusitis revealed the appearance of neutrophil clusters in the sinonasal air space, infiltration of eosinophils and iNOS-positive inflammatory cells in the mucosa, areas of epithelial loss, and goblet cell hyperplasia in the epithelium. This rat model of PAF-induced rhinosinusitis may be applied for better understanding of the role of PAF in the pathogenesis of rhinosinusitis.
Administration, Intranasal↗
Theophylline and acetazolamide reduce sleep-disordered breathing at high altitude.
A randomised, double-blind, placebo-controlled study was conducted to evaluate the effects of theophylline and acetazolamide in the treatment of sleep-disordered breathing (SDB) after fast ascent to high altitude (3,454 m). The study was conducted at a high-altitude research laboratory and included 30 healthy male volunteers. Study medication was either oral slow release theophylline (2x250 mg x day(-1)), oral acetazolamide (2x250 mg x day(-1)) or a matched placebo tablet. Polysomnographic measurements were performed during two consecutive nights, and acute mountain sickness, pulse rate, oxyhaemoglobin saturation and arterial blood gases were assessed three times a day. Without active medication, the apnoea/hypopnoea index (AHI) was highly pathological (median 16.2 x h(-1), range 2-92). Both theophylline and acetazolamide normalised SDB (median AHI 2.5 x h(-1), range 0-11; 4.2 x h(-1), range 0-19, respectively) and reduced oxyhaemoglobin desaturations during sleep (median desaturation index placebo 41.5 x h(-1), range 6-114; acetazolamide 6.5 x h(-1), range 3-28; theophylline 8.5 x h(-1), range 3-32). Compared with the high amount of central apnoeas or hypopnoeas, the number of obstructive events during sleep was very low in all groups (<4 x h(-1)). In contrast to theophylline, acetazolamide significantly improved basal oxyhaemoglobin saturation during sleep (86.2 +/- 1.7% versus 81.0 +/- 3.0%). The authors conclude that both oral slow release theophylline and acetazolamide are effective to normalise high-altitude sleep-disordered breathing.
Acetazolamide↗
Eformoterol n-of-1 trials in chronic obstructive pulmonary disease poorly reversible to salbutamol.
AIMS: Benefits of long acting beta 2 agonists are unclear for severe chronic obstructive pulmonary disease (COPD) patients with poor response to short acting bronchodilators. We aimed to evaluate 1) effects of eformoterol in such patients using a 'n-of-1' double crossover study design, and 2) aggregate data as a double-blind, double crossover randomized control trial. METHODS: Subjects with forced expiratory volume in one second (FEV1) < 60% predicted, and poor response to short acting bronchodilators were studied six times over 18 weeks. During that time they were prescribed four weeks of either eformoterol or placebo, followed by the alternate, and then a second crossover. Four-weekly measures included six minute walk distance (6MWD), FEV1, previous two weeks of symptoms, and chronic respiratory questionnaire (CRQ) including treatment goal items. RESULTS: Of 27 original subjects (21 male, mean age of 70 years, five smokers, mean prebronchodilator FEV1 36% predicted), one subject had clinically significant concordant improvement in the CRQ dyspnoea domain and 6MWD (by 51 metres), but not for other outcomes. There were no concordant improvements in any other subjects. Aggregate double crossover data analysis demonstrated no improvement in any outcome measures. CONCLUSIONS: The 'n-of-1' study design and aggregate data analysis demonstrated lack of benefit from eformoterol in COPD patients with poor response to short acting bronchodilators.
Adrenergic beta-Agonists↗
Preoperative treatment of acromegaly with long-acting somatostatin analog SMS 201-995: shrinkage of invasive pituitary macroadenomas and improved surgical remission rate.
Ten patients with previously untreated acromegaly and invasive pituitary macroadenomas were treated with the long-acting somatostatin analog SMS 201-995 (Sandoz) for 3-30 weeks before transsphenoidal or subfrontal pituitary adenomectomy. Preoperatively, treatment with SMS 201-995 reduced mean 24-h plasma GH concentrations from 8.5-66.7 to below 4.6 micrograms/L in eight patients and by 60-80% in the remaining two patients. Pituitary tumor size decreased 20-54%. Morphologically, the tumors showed decreased total cell, cytoplasmic, and nuclear areas; varying degrees of perivascular fibrosis; and dense granularity. Postoperatively, plasma GH and insulin-like growth factor I concentrations fell into the normal range, and GH dynamics became normal in eight patients. In the remaining two patients mild GH hypersecretion persisted after surgery (mean fasting and random plasma GH, 6.1 and 7.9 micrograms/L), and in one of them GH secretion became normal 1 yr after pituitary irradiation. Thus, preoperative administration of SMS 201-995 consistently induced shrinkage of GH-producing pituitary tumors, and the apparent remission rate was high in the treated patients.
Acromegaly↗
Leukotriene synthesis inhibition and receptor blockade do not inhibit hypoxic pulmonary vasoconstriction in sheep.
Several lines of evidence suggest that leukotrienes may be mediators of hypoxic pulmonary vasoconstriction (HPV). However, the effect of leukotriene inhibition on HPV remains controversial. The present study investigated the effect of leukotriene synthesis inhibition and receptor blockade on HPV in the halothane-anesthetized sheep. After initial baseline measurements, the pulmonary pressor response to 15 min of global hypoxia (FIO2 = 0.13) was measured. A second set of baseline measurements was obtained and the sheep then received the combined cyclooxygenase/lipoxygenase inhibitor BW755C, the selective lipoxygenase inhibitor U60257, or the leukotriene receptor antagonist LY171883. Hemodynamic measurements were obtained after drug administration and during a subsequent hypoxic challenge (FIO2 = 0.13). Initial hypoxic challenge increased pulmonary artery pressure 68% and increased pulmonary vascular resistance 104%. Pulmonary hemodynamics after recovery from hypoxia were similar to initial baseline values. Drug administration had no significant hemodynamic effect. Hypoxic challenge after drug administration resulted in a pulmonary pressor response identical to the initial hypoxic challenge. Because leukotriene synthesis inhibition and receptor blockade did not alter the response to hypoxia, we conclude that leukotrienes are not obligatory mediators of HPV. A critical review of the literature supports a modulatory rather than an obligatory role for leukotrienes in HPV.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
Production of leukotrienes from mouse peritoneal macrophages by treatment with a neutral subfraction of bakers' yeast mannan.
We concluded that a neutral subfraction of mannan from bakers' yeast (Saccharomyces cerevisiae wild type strain), abbreviated as WNM, was able to induce the release of leukotrienes from mouse peritoneal macrophages (M phi). The culture supernatant fluid of M phi from normal mice cultured with WNM caused a marked contraction of guinea pig ileum. This activity was inhibited by pretreatment of M phi with inhibitor of phospholipase A2 or lipoxygenase before M phi were treated with WNM, and by treatment of the incubation bath with a slow reacting substance antagonist, FPL55712. On the other hand, pretreatment of M phi with a cyclooxygenase inhibitor potentiated contractile response of ileum by culture supernatant fluid of M phi. A high performance liquid chromatographic analysis of a culture supernatant fluid of M phi treated with WNM demonstrated the presence of leukotrienes C4 and D4, and their related compounds.
Animals↗
[Effect of traxanox sodium on inflammatory response].
Traxanox was inactive against classic acute and subacute inflammation models such as carrageenin paw edema, UV erythema, 6-hr Evans blue-carrageenin (E-C) pleurisy and cotton pellet granuloma formation, and it failed to inhibit the production of prostaglandin E2 and a slow reacting substance from rat peritoneal leucocytes which phagocytize killed bacteria in vitro. On the other hand, traxanox inhibited the anaphylactoid reaction and decreased the pleural fluid in 24-hr E-C pleurisy. Traxanox (100 mg/kg, p.o.) also showed a tendency to suppress dextran edema and cotton pellet granuloma formation in adjuvant arthritis (AA) in rats. In experimental models of delayed type hypersensitivity (DTH), traxanox (100 mg/kg, p.o.) inhibited the accumulation of the exudate and the leucocyte migration in B. pertussis-induced pleurisy in rats. Traxanox (50 mg/kg) did not show any effect on AA in Lewis rats when administered orally for 21 days after the adjuvant inoculation, but the combined administration of traxanox with hydrocortisone (10 mg/kg, p.o.) or indomethacin (0.25 mg/kg, p.o.) resulted in a synergistic inhibition of AA. When the administration of traxanox was started 21 days before the adjuvant inoculation, it inhibited AA in a dose-dependent manner (50-100 mg/kg, p.o.). On the other hand, traxanox (100 mg/kg, p.o.) enhanced the concanavalin A-induced DTH-like skin reaction in guinea pigs. These results indicate that the mode of action of traxanox on inflammatory responses resembles that of D-penicillamine or levamisole, so that it may prove to be clinically effective in treating rheumatoid arthritis.
Anaphylaxis↗
Inhibitory effect of N-(3,4-dimethoxycinnamoyl)anthranilic acid on release of SRS from alveolar macrophages in vitro.
The effects of N-(3,4-dimethoxycinnamoyl)anthranilic acid (N-5') on the release of the slow-reacting substance (SRS) by zymosan- or Ca ionophore-stimulated rat and human alveolar macrophages (AM) were examined in vitro. Disodium cromoglycate (DSCG) was used as a control. N-5' at concentrations of 10(-4)-10(-3) M significantly inhibited the release of SRS from both rat and human AM stimulated by zymosan. N-5' had almost the same inhibitory effect when added to the AM culture system at any time from 180 min before to 30 min after the addition of zymosan. N-5' (10(-4)-10(-3) M) also significantly inhibited the release of SRS by Ca ionophore-stimulated rat AM. N-5' (10(-6)-10(-3) M) had no significant effect on phagocytosis of yeast particles by rat AM. DSCG (10(-6)-10(-3) M) did not inhibit the release of SRS from the zymosan-stimulated rat AM. N-5' was concluded to have a relatively specific inhibitory effect on the non-immunological release of SRS from stimulated AM. It is postulated that N-5' inhibits the process of release of SRS from AM by acting after the initial stage.
Animals↗
The lung mast cell: its physiology and potential relevance to defense of the lung.
The mast cell, located at mucosal surfaces and surrounding venules, is uniquely positioned to respond rapidly to insults to the host by mediating the development of a wide-ranging inflammatory response. Activaton of the mast cell releases preformed granule-associated chemical mediators and generates de novo biologically active materials. The properties of the mast cell mediators permit development of both acute and prolonged inflammatory responses. the immediate response is characterized by edema and the delayed response by leukocyte infiltration and vascular damage. the mast cell mediators responsible for these inflammatory events are characterized functionally. The vasoactive/smooth muscle reactive mediators include preformed histamine and serotonin and newly-generated platelet activating factor, slow reacting substance of anaphylaxis and prostaglandins. Chemotactic mediators include eosinophil-selective ECF-A and ECF-oligopeptides, neutrophil-selective NCF, and lipid chemotactic mediators with broad specificity. These factors induce directed migration and localization of leukocytes. The mast cell releases the structural proteoglycan, heparin, which is anticoagulant and inhibits complement. Released mast cell enzymes include chymotryptic and tryptic proteases, arylsulfatase, beta-glucuronidase, and hexosaminidase. The proteolytic enzymes may activate inflammatory pathways while the others degrade ground substance. The capacity of the mast cell to enhance vascular permeability, to cause the influx of regulatory or inflammatory leukocytes, and to provide a variety of active enzymes permits regulation of inflammatory events at the site of tissue injury.
Animals↗
Mast cell mediators and asthma.
Mast cells are found beneath the basement membranes, near blood vessels in the submucosa, adjacent to submucous glands, scattered throughout the muscle bundles, in the interalveolar septa and in the bronchial lumen. The evidence that mast cells and mast cell-derived mediators play a role in allergic and non-allergic asthma is discussed. In allergic individuals, inhalation of specific allergens leads to mast cell degranulation and release of mediators. Many of the pathologic features of asthma may be attributed to the effects of mast cell-derived mediators. Their role is clear in allergic asthma and the presence of mast cell derived mediators in the plasma of individuals with exercise-induced and nocturnal asthma suggests involvement in other forms of asthma as well.
Animals↗
Mechanisms in anti-inflammation and resolution: the role of lipoxins and aspirin-triggered lipoxins.
Multicellular host responses to infection, injury or inflammatory stimuli lead to the formation of a broad range of chemical mediators by the host. The integrated response of the host is essential to health and disease; thus it is important to achieve a more complete understanding of the molecular and cellular events governing the formation and actions of endogenous mediators of resolution that appear to control the duration of inflammation. Lipoxins are trihydroxytetraene-containing lipid mediators that can be formed during cell-cell interactions and are predominantly counterregulators of some well-known mediators of inflammation. Since this circuit of lipoxin formation and action appears to be of physiological relevance for the resolution of inflammation, therapeutic modalities targeted at this system are likely to have fewer unwanted side effects than other candidates and current anti-inflammatory therapies. Here, we present an overview of the recent knowledge about the biosynthesis and bioactions of these anti-inflammatory lipid mediators.
Animals↗
Evaluation of a single-dose, extended-release epidural morphine formulation for pain after knee arthroplasty.
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Analgesia, Epidural↗
Antiasthmatic drugs I: pathophysiological and clinical pharmacological aspects.
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Adrenal Cortex Hormones↗