Bronchial hyper-reactivity in atopic patients during H2-receptor blocker treatment

Bronchial reactivity after Cimetidine treatment was evaluated by the histamine provocation test in 24 patients with atopic bronchial asthma and 10 patients with peptic ulcer. Anti-IgE induced histamine release from isolated basophils was also investigated. After blockade of H₂ receptors, an increase of bronchial reactivity and an exacerbation of clinical symptoms were observed in 4 asthmatic patients [17%]. A moderate increase in bronchial reactivity without exacerbation of asthma symptoms was observed in 16 other patients [66%]. In some of the patients treated with Cimetidine an enhancement of IgE-induced histamine release from isolated basophils was observed.     

Effect of tumor necrosis factor receptor binding protein on cell infiltration induced by lipopolysaccharide and sephadex beads in guinea pig lung

In the present study, the effect of a tumor necrosis factor receptor binding protein (TNFbp) on the cell infiltration induced by lipopolysaccharide (LPS) and Sephadex beads in guinea pig lung was examined. The intratracheal injection of LPS (2.5g) induced a six-fold increase in total cell number recovered in bronchoalveolar lavage (BAL) fluid at 24 hr. This increase in bronchopulmonary inflammation was mainly due to a neutrophil and macrophage infiltration, representing 60% and 35% of the total cells, respectively. The intravenous or intratracheal injection of Sephadex beads to guinea pigs induced a three-fold increase in total cell number recovered in BAL at 24 h and was characterized by a prominent eosinophil, macrophage, and neutrophil infiltration representing 36%, 42%, and 16% of the total cells, respectively. In addition, bronchial tissues isolated from Sephadex-treated guinea pigs showed an increased in vitro reactivity to both histamine and acetylcholine. TNFbp (1–50g) induced a dose-dependent inhibition of cell infiltration induced by LPS. In contrast TNFbp neither attenuated the bronchopulmonary cell infiltration observed 24 h following intravenous or intratracheal administration of Sephadex beads nor inhibited the increase in bronchial reactivity. These results show that TNF plays an important role in cell infiltration induced by LPS, but not that induced by Sephadex, in the guinea pig lung.     

Early Bronchial Hyperresponsiveness Following Injection of Sephadex Beads in the Guinea Pig: Involvement of Platelet Activating Factor and Thromboxane A2

The effects of an intravenous injection (i.v.) of Sephadex beads (20 mg kg^–1) were examined on bronchial responsiveness to ACh (1–200 g kg^–1 i.v.) as well as on cell accumulation in guinea-pig lung. Bronchial hyperreactivity to ACh, measured as increase in pulmonary insufflation pressure (PIP), was observed 3 h following the i.v. injection of Sephadex beads. However, no significant increase in bronchial reactivity to ACh was measured at 6 and 12 h following Sephadex injection. A second later increase in bronchial hyperresponsiveness was observed at 24 h. Bronchoalveolar lavage performed at 3 h following Sephadex treatment showed that there was no significant increase in total or differential cell number. At 6 h and 12 h, a significant increase in total cell counts was observed. At 24 h, a greater than 5-fold increase in cell number was observed and was related to a marked eosinophil, neutrophil and macrophage infiltration. A platelet-activating factor (PAF) antagonist, CV-3988 (10 mg kg^–1 i.v.), and a thromboxane A₂ (TxA₂) antagonist, L655,240 (10 mg kg^–1 i.v.), significantly attenuated the Sephadex-induced bronchial hyperresponsiveness to ACh observed at 3 h. The results show that an i.v. injection of Sephadex beads in guinea pigs can induce an early bronchial hyperresponsiveness to ACh that is mediated by the release of both PAF and TxA₂ and is independent of airway cell infiltration.     

The influence of Cimetidine and Ranitidine on basophil histamine release and bronchial reactivity in asthmatic patients

Anti-IgE induced histamine release from isolated basophils after Cimetidine and Ranitidine administration was evaluated in 22 patients with atopic bronchial asthma.The histamine provocation test after Ranitidine treatment in 10 patients with atopic bronchial asthma and 10 patients with peptic ulcer was also performed.Investigationsin vitro revealed that Cimetidine and Ranitidine in low concentrations had an inhibitory effect whereas in concentrations of over 10^–6 M and 10^–4 M, respectively, they enhanced histamine release.Investigationsin vivo after administration of Ranitidine showed that it does not cause marked changes in the bronchial reactivity in patients with bronchial asthma and any change in patients with peptic ulcer.These preliminary studies seem to suggest that in patients with atopic bronchial asthma and concomitant peptic ulcer Ranitidine is preferable to Cimetidine in the treatment of digestive tract disorders.This work was supported by the Polish Academy of Science (grant Nr 06.03).     

Bronchial response to methacholine and histamine in monkeys with beta adrenergic blockade

The possibility has been investigated that propranolol administration could alter bronchial reactivity to methacholine and histamine in monkeys (Macaca fuscata and Macaca fascicularis). The impedance of the total respiratory system was measured by the forced 3-HZ oscillation method through an endotracheal tube. Methacholine and histamine dose-dependently increased the impedance in monkeys irrespective of the route of administration (inhalation of aerosol or intravenous injection). Propranolol treatment increased the bronchial response to intravenously injected methacholine and caused no significant change in the bronchial response to aerosolized methacholine. No marked difference was observed in the bronchial response to histamine due to treatment with propranolol regardless of whether administered by intravenous injection or aerosol challenge.     

The role of H2-receptors in bronchial reactivity in atopic asthma

The aim of the present study was to evaluate lung function and bronchial reactivity during therapy with the H₂-blockers, cimetidine and ranitidine, in order to determine the role of H₂-receptors in the bronchial response of asthmatic patients. Bronchial reactivity was evaluated by the histamine provocation test before, and 3 or 6 days after administration of cimetidine (800 mg per day) or ranitidine (300 mg per day). It was shown that after 6 days treatment, an increase in bronchial reactivity occured in 85% of the patients treated with cimetidine and in 64% of the patients treated with ranitidine. These results seem to confirm the presence of H₂ receptors in the bronchial tree of asthmatic patients. Blockade of these receptors causes an increase in bronchial reactivity and potential exacerbation of the asthmatic symptoms.This work was supported by the Polish Academy of Sciences (Grant No. 06.03).     

Long-term intense exposure to grass pollen can mask positive effects of allergenic immunotherapy on non-specific bronchial hyperresponsiveness

Introduction

There are many potential factors that can modulate bronchial reactivity, including exposure to allergens, viral infections, and medications. The aim of this study was to analyze the effect of grass pollination intensity on the bronchial reactivity in seasonal allergic rhinitis (SAR) patients subjected to subcutaneous allergenic immunotherapy (SCIT).

Material and methods

This study, performed between 2005 and 2008, included 41 patients with confirmed sensitivity to grass pollens and predominating symptoms of SAR, randomly assigned to desensitization by pre-seasonal or maintenance SCIT. Bronchial provocation challenge with histamine was performed before the onset of immunotherapy, and repeated three times after each pollen season covered by this study. Bronchial reactivity was analyzed with regard to grass pollination intensity in 2005–2008 (air concentration of grass pollen grains, seasonal number of days when air concentration of grass pollen reached at least 20 or 50 grains per 1 m³).

Results

After 3 years of SCIT, a significant decrease in bronchial responsiveness was observed in the analyzed group as confirmed by an increase in PC₂₀ FEV₁ histamine values (p = 0.001). An inverse tendency was observed after 2 years of SCIT, however. This second year of SCIT corresponded to the 2007 season, when a significantly higher number of days with at least 50 grains of pollen per 1 m³ of air was recorded.

Conclusions

Fluctuations in pollination intensity observed during consecutive years of immunotherapy can influence bronchial reactivity in patients subjected to SCIT (ISRCTN Register: ISRCTN 86562422).     

The quantification of IgE antibody specific for ragweed Antigen E (AgE) from the basophil surface in patients with ragweed pollenosis

IgE antibody specific for AgE (IgE—AgE) was eluted from human basophils at acid pH and quantified by its binding of ¹²⁵I AgE in antigen excess. The quantity of Ige—AgE recovered from 30 ml of blood ranged from 0.08 ng to 10.3 ng representing 500 to 56,000 molecules IgE—AgE per basophil. The number of molecules of IgE—AgE per basophil was compared to plasma IgE—AgE, total plasma IgE and leucocyte histamine release in response to AgE.

The ratio of plasma IgE—AgE to basophil bound IgE—AgE ranged from 100 to 4000, indicating that there are a limited number of IgE receptors on the basophil surface as contrasted to the concentration of IgE in the plasma. There was no correlation between IgE—AgE in plasma and the number of molecules of IgE—AgE per basophil. However there was a significant correlation between the ration of IgE—AgE to total IgE in plasma and the number of IgE—AgE molecules per basophil.

Two measures of leucocyte histamine release in response to AgE, cell reactivity (maximum per cent histamine release attainable) and sensitivity (lowest antigen dose leading to 50% release), were compared to the number of IgE—AgE molecules per basophil. Cell reactivity was dependent on the number of IgE—AgE molecules per basophil. Only 2500 molecules IgE—AgE per basophil were required to reach a cellular reactivity of 50%. Cell sensitivity to AgE was not correlated with the number of molecules IgE—AgE per basophil which indicated that other factors played a role in determining the sensitivity of a population of basophils to antigenic stimulation by AgE.

     

The relationship between bronchial histamine reactivity and atopic status

It has been proposed that increased production of IgE, a feature of atopy, is a cause of the non-specific bronchial hyper-reactivity that is characteristic of asthma. This hypothesis was examined by selecting groups of subjects with asthma or rhinitis and a group of healthy control subjects and studying the relationship between their bronchial histamine reactivity and their atopic status. In none of the groups tested was there a significant association between the degree of bronchial histamine reactivity and either the serum level of total IgE or the number of extracts of aero-allergens giving positive prick test reactions.     

Adenosine potentiates neurally- and histamine-induced contraction of canine airway smooth muscle

We studied the effect of adenosine on airway reactivity of isolated canine bronchial smooth muscle under isometric conditions in vitro. Administration of adenosine and its analogs increased the contractile responses of bronchial segments to electrical field stimulation in a dose-dependent fashion, where the rank order potency was N-ethylcarboxamideadenosine greater than adenosine greater than N-cyclohexyladenosine, but had no effect on those to exogenous acetylcholine. This potentiation was more pronounced at relatively low than at high stimulus frequencies, the maximal increase from the baseline responses being 56.3 +/- 9.6% at 1 Hz (mean +/- SE, p less than 0.01). Adenosine also increased the histamine-induced contraction causing a leftward shift of the histamine dose-response curves, an effect that was abolished in the presence of atropine. These results suggest that adenosine potentiates airway responsiveness to vagal stimulation and to histamine through the activation of prejunctional A2 receptor, probably involving the accelerated release of acetylcholine from the cholinergic nerve terminals.     

Sputum eosinophilia: an early marker of bronchial response to occupational agents

Background: False‐negative responses to specific inhalation challenge (SIC) with occupational agents may occur. We explored whether assessing changes in sputum cell counts would help improve the identification of bronchial reactivity to occupational agents during SICs. Methods: The predictive value of the changes in sputum cell counts after a negative FEV₁ response to a first challenge exposure to an occupational agent was determined using the changes in airway calibre observed during repeated challenges as the ‘gold standard’. The study included 68 subjects investigated for work‐related asthma in a tertiary centre. After a control day, the subjects were challenged with the suspected occupational agent(s) for up to 2 h. All subjects who did not show an asthmatic reaction were re‐challenged on the following day. Additional challenges were proposed to those who demonstrated a ≥ 2% increase in sputum eosinophils or an increase in nonspecific bronchial hyperresponsiveness to histamine after the second challenge day. Results: Six of the 35 subjects without changes in FEV₁ on the first challenge developed an asthmatic reaction on subsequent challenges. ROC analysis revealed that a >3% increase in sputum eosinophils at the end of the first challenge day was the most accurate parameter for predicting the development of an asthmatic response on subsequent challenges with a sensitivity of 67% and a specificity of 97%. Conclusions: An increase in sputum eosinophils is an early marker of specific bronchial reactivity to occupational agents, which may help to identify subjects who will develop an asthmatic reaction only after repeated exposure.     

Mast cell tryptase as a mediator of hyperresponsiveness in human isolated bronchi

BACKGROUND: Although the role of mediators and cytokines produced by mast cells is well established in asthmatic bronchial inflammation, the contribution of mast cell-derived proteases to the development of hyperresponsiveness remains unclear. There have been reports indicating that tryptase alters the mechanical activity of animal airway smooth muscle or spontaneously sensitized human isolated airways. OBJECTIVE: The aim of this study was to analyse the effect of purified mast cell tryptase on non-sensitized human isolated bronchi. METHODS: Both central and peripheral bronchi, dissected from lung specimens obtained at thoracotomy, were studied in terms of both mechanical activity i.e. isometric contraction in response to a variety of agonists and distribution of inflammatory cells i.e. immunohistochemistry. RESULTS: In both proximal and distal bronchi, the reactivity to histamine was significantly increased by a previous incubation in the presence of 1 microg/mL of tryptase (increase in maximal force, DeltaFmax was 12.1 +/- 3.8%, and 8.8 +/- 3.1%, respectively). This effect of tryptase on histamine-induced contraction was completely abrogated in the presence of the protease inhibitor benzamidine (100 micromol/L). Histological examination of specimens exposed to tryptase demonstrated an increase in mast cell number within the subepithelial tissue whereas mast cell numbers in the epithelial layer concomittently decreased. CONCLUSION: These results indicate that human mast cell tryptase alters the contractile response of non-sensitized human isolated bronchi and that this alteration is accompanied by a change in the mast cell distribution within the airway wall.     

Parainfluenza-3 infection of the guinea pig airways induces respiratory airway hyperreactivityin vitro

Guinea pigs were inoculated intra-tracheally with bovine parainfluenza type 3 virus (PI-3) to investigate airway responsiveness to histamine and arecolinein vitro. Two days after saline or PI-3 inoculation no difference in the reactivity of the tracheal spirals was observed after cumulative concentration/response curves with both drugs. Similarly, contractions of parenchymal strips, induced by histamine, did not differ between both groups. However, 4 days after PI-3 inoculation the histamine induced contraction of the tracheal spirals was increased by 47% and the arecolinc induced contractions by 32% as compared to the control group. Further, the contractions induced by histamine in parenchymal strips were significantly enhanced (p<0.01) in the PI-3 treated group. In conclusion, PI-3 infection of guinea pig respiratory tract induces hyperreactivity of the central and peripheral airwaysin vitro.     

Relationship between mediator release from human lung mast cells in vitro and in vivo

There is now compelling evidence to incriminate bronchial mast cells in the pathogenesis of bronchoconstriction of allergic asthma. Human mast cells isolated from lung tissue or bronchoalveolar lavage release histamine and generate eicosanoids upon IgE-dependent activation. In this paper we present data that raise doubts about the significance of phospholipid methylation in IgE-dependent activation-secretion coupling and provide evidence that drugs such as 3-deazaadenosine inhibit mediator secretion by inhibiting phosphodiesterase, in addition to inhibiting putative methylation pathways. Activation of human mast cells and basophils also stimulates adenylate cyclase to increase levels of cyclic AMP, which, on the basis of pharmacological manipulation with purine nucleosides, we believe is involved in the progression of the secretory response. Human lung cells also generate both cyclo- and lipoxygenase products of arachidonate upon Ca++-dependent stimulation with complex interactions occurring between these pathways in the presence of the leukotriene inhibitor, Piriprost. The role of mast cells in the immediate airway response to inhaled allergens in asthma was demonstrated by showing an interaction between nonspecific bronchial reactivity and mast cell reactivity in predicting the airway response upon antigen inhalation. Further confirmation of this concept was obtained by showing an inverse relationship between the release of histamine and neutrophil chemotactic factor (NCF) into the circulation induced by antigen challenge, and nonspecific airway reactivity. The identification of significant increases in circulating mediators following antigen provocation of patients with seasonal asthma enabled the effects of drugs used in the treatment of asthma to be compared on airway calibre and mast cell mediator release. Sodium cromoglycate partially inhibited the airway and plasma histamine responses with antigen, but totally inhibited the increases in NCF. Salbutamol completely inhibited all responses, while ipratropium bromide, which produced the same bronchoconstriction as achieved with salbutamol, had no effect. The potent H1-antagonist astemizole partially inhibited bronchoconstriction without affecting histamine release. Antigen provocation produced a significant increase in circulating levels of the 13,14-dihydro-15-keto metabolite of PGF2 alpha which could originate from mast cell-derived PGD2. In both retrospective and prospective studies, a close relationship was shown between nonspecific bronchial reactivity and resting airway calibre in asthma.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of dithiothreitol on the isolated rabbit mesenteric artery

Rabbit mesenteric artery strips exposed to 10^–3 M dithiothreitol (DTT) were contracted with a series of concentrations of histamine and 2-pyridylethylamine (PEA). DTT exposure increased the sensitivity to histamine 100-fold but increased the sensitivity to PEA only 4-fold. DTT did not reduce dimaprit-induced relaxations, but reduced histamine-induced relaxations. Following a high concentration of histamine (10^–3 M), DTT itself produced a sustained, slowly developing contraction (29±6.8% of the maximal contraction) relaxed by 7×10^–6 M mepyramine but not by 10^–6 M phentolamine. Metiamide (3×10^–3 M) potentiated DTT-induced contractions (29±6.8 before, 57±7.5% after metiamide, as a percent of maximal contraction). Changing the bathing fluid and repeating DTT exposure slowly relaxed previously contracted strips. DTT did not prevent the increase in sensitivity of relaxant histamine receptors on exposure to cold. We conclude that DTT, in addition to potentiating histamine H₁-receptor responses, releases histamine presumably from non-mast cell pools when they are loaded with a high concentration of exogenous histamine.     

Bronchial histamine reactivity: its relationship to the reactivity of the bronchi to allergens

The aim of this study was to examine the proposal that the magnitude of the response of the bronchi to an immediate allergic reaction depends not only on the degree of sensitization of the bronchi by allergen specific IgE antibody but also on the reactivity of the bronchi to the vasoactive mediators which are released during immediate allergic reactions. This was done by determining the bronchial reactivity to Dermatophagoides pteronyssinus and to histamine of both symptomatic and asymptomatic groups of atopic subjects who had comparable serum levels of D. pteronyssinus specific IgE. Positive bronchial responses to the D. pteronyssinus extract were recorded with both the symptomatic and asymptomatic subjects, the mean bronchial threshold dose of allergen being significantly higher in the asymptomatic than in the asthmatic patients. There was a highly significant correlation between the serum level of allergen specific IgE and the bronchial threshold dose of allergen extract and also between the bronchial threshold dose of allergen extract and of histamine in all groups of subjects. The ability to predict bronchial reactivity to the allergen from the serum level of allergen specific IgE within each group was significantly better if the bronchial reactivity to histamine was included in the correlation analysis. This supports the hypothesis that whether a particular subject who is producing specific IgE antibody will develop symptoms on the inhalation of that allergen depends not only on the amount of allergen which he inhales and on the degree of sensitization of his bronchi but also on the reactivity of his bronchi to the vasoactive mediators which are released by allergen–IgE interaction.     

The importance of eosinophil activation for the development of allergen-induced bronchial hyperreactivity in conscious,unrestrained guinea-pigs

Using a newly developed guinea-pig model of asthma, characterized by allergen-induced early and late phase asthmatic reactions, bronchial hyperreactivity (BHR) and airway inflammation, the importance of eosinophil activation for the development of BHR to inhaled histamine was investigated at 6 h (after the early reaction) and 24 h (after the late reaction) after allergen provocation. Eosinophil activation was assessed by a sensitive kinetic assay for eosinophil peroxidase (EPO) activity, suitable for bronchoalveolar lavage (BAL) analysis. A significant 2±9-fold (P < 0±01) increase in bronchial reactivity to histamine was observed at 6 h after allergen exposure, which was associated with a 2±9-fold increase in the number of eosinophils (P < 0±05) and a 6±7-fold increase in EPO activity (P < 0±01) in the BAL fluid. At 24 h after allergen exposure the bronchial reactivity to histamine was lower (1±7-fold), but still significantly enhanced (P < 0±01). By contrast, the number of eosinophils was further increased compared with 6 h after provocation (3±8-fold, P < 0±05), while the EPO activity remained stable at 6 h levels. The number of eosinophils was significantly correlated with EPO activity at 6 h (r = 0±62; P < 0±05), but not at 24 h after provocation. No significant correlation was observed between the number of eosinophils in the BAL fluid and BHR to histamine at either time point. Remarkably, EPO activity was significantly correlated to BHR at 24 h (r = 0±66; P < 0±004), but not at 6 h after provocation. These results indicate that: newly infiltrated eosinophils have the highest activation state during the early asthmatic reaction; EPO may play a role in the development of BHR to inhaled histamine after the late reaction and that besides EPO, additional mechanisms may contribute to BHR to histamine after the early asthmatic reaction.     

Sodium cromoglycate in histamine and methacholine reactivity in asthma

The effect of increasing concentrations of inhaled sodium cromoglycate (SCG) (2, 10, 20 and 40 g/l) on histamine and methacholine bronchial reactivity was studied in nine patients with extrinsic bronchial asthma. The responses to histamine and methacholine were expressed in terms of provocative concentrations producing 20% fall in the FEV₁ (PC₂₀)- The PC₂₀ for histamine and methacholine was unaffected by all the concentrations of SCG used in the study. These results suggest that the effect of SCG on the bronchial smooth muscle or on the muscarinic receptors is minimal.     

Recurrent nocturnal asthma after bronchoprovocation with Western Red Cedar sawdust: association with acute increase in non-allergic bronchial responsiveness

Recurrent nocturnal asthma following a single exposure to Western Red Cedar sawdust was documented by measurements of peak flow rates in two sensitized subjects. The nocturnal asthma followed a dual asthmatic response in the first subject and a late (non-immediate) asthmatic response in the second. Both subjects developed a 10-fold reduction in the dose of histamine required to decrease the FEV₁ by 20%. This cedar-induced increase in non-specific bronchial reactivity was maximal at the time of the recurrent nocturnal asthma, and persisted after nocturnal asthma had ceased and after FEV₁ had returned to normal. We hypothesize that the enhanced non-specific bronchial reactivity which occurs following late asthmatic responses to bronchial challenge is the cause of recurrent nocturnal asthma following single exposure to a sensitizing agent.     

Morphological and secretory properties of bronchoalveolar lavage mast cells in respiratory diseases

We have studied various functional and morphological characteristics of mast cells obtained in bronchoalveolar lavage from fifty-two patients with several lung diseases. The percentage of mast cells ranged from 0.04 to 0.6% (bronchial carcinoma). 0.05–0.3% (sarcoidosis), 0.06–0.25% (asthma), 0.04–1.8% (miscellaneous) and 0.02–0.04% (normals). There were no significant differences in the mast cell counts between the disease groups. Lung mast cells exhibited heterogeneity of size, shape and intensity of staining. Cells from thirty-seven subjects were further studied for total histamine content and histamine release using various secretagogues. There was a significant correlation (P<0.001) between the histamine content of the total lavage cell population and mast cell counts. The calculated mean histamine content per mast cell was 6.35 pg. Histamine was released in a dose-dependent fashion after stimulation with anti-IgE, calcium ionophore and phorbol myristate acetate with a time course of histamine release characteristic of the mast cell. Unlike peripheral blood basophils, no release was observed following incubation with f-met-leu-phe (10^?6-10^?8m ) and neither cell type released histamine following incubation with 48/80 (10 μg/ml). Inhibition of anti-IgE-induced histamine release was obtained following pre-incubation with salbutamol (10^?4-10^?6m ). These studies indicate that bronchoalveolar lavage is a suitable model for the study of human lung mast cells.