Histamine Aerosol Research Articles

Bronchial challenge tests: usefulness, availability and limitations

Indirect challenges to assess bronchial hyperresponsiveness are being increasingly used both for research and for assessment in the routine pulmonary function laboratory. “Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract with or without inducing microvascular leakage. Because the responses to these challenges are modified or completely inhibited by inhaled steroids, the airway response to the challenges may be a closer reflection of active airway inflammation” (fig. 1) [1]. In contrast, the direct tests, inhaled aerosols of histamine and methacholine act directly on receptors on the bronchial smooth muscle to cause contraction. While sensitive for detecting bronchial hyperresponsiveness a positive response to these agents is not specific for identifying asthma particularly at the higher concentrations. The best known of the indirect challenges is exercise. Other indirect challenges include eucapnic voluntary hyperpnoea, mannitol, adenosine monophosphate and hyperosmolar saline. All these indirect challenges are associated with release of mediators of bronchoconstriction. For this reason they have the potential to be used to identify presence of inflammatory cells particularly mast cells [2]. Figure 1 The events that lead to airway narrowing and a reduction in forced expiratory volume in 1 s in response to different indirect challenge tests. While hyperpnoea, mannitol and 4.5% saline all act to increase osmolarity that causes mediators to be released, adenosine acts to release mast cell mediators through a specific receptor on the mast cell. ASL: airway surface liquid; FEV1: forced expiratory volume in 1 s. Modified from [2] with permission from the publisher. ### Usefulness Exercise testing is used to diagnose exercise-induced bronchoconstriction (EIB). The term EIB describes the transient increase in airways resistance that follows vigorous exercise. EIB is thought to result from transient dehydration of the airway surface in response to conditioning the inspired …

Method for recording respiratory changes induced in guinea-pigs by aerosols of histamine or of specific antigen, and for assessing drugs which antagonise bronchoconstriction

Abstract A lightly-anaesthetised guinea-pig is made to breathe an aerosol of histamine or of specific antigen pumped into a breathing chamber. The guinea-pig’s respiration produces pressure changes which are recorded on a smoked drum. Isoprenaline and the antihistamine thenyldiamine, administered as aerosols or by injection, have been used to inhibit the reduction in “tidal volume” due to the bronchoconstrictor agents.

Investigation of changes in the lipid content of guinea-pig lung after anaphylaxis

A detailed analysis of the lipid content of guinea-pig lung following anaphylaxis in vivo induced by aerosolized antigen showed a significant reduction in all fractions. Anoxia induced by nitrogen produced reductions in the partial glycerides and ethanolamine phospholipid. Exposure to an aerosol of histamine caused a reduction in all but the choline phospholipid and sphingolipid fractions. It was concluded that the losses of choline phospholipid and sphingolipid result from the anaphylactic reaction and not from subsequent changes.

The regulatory role of vitamin C on the adrenal function and resistance to histamine aerosol in the scorbutic guinea-pig.

The regulatory role of vitamin C on the adrenal function and resistance to histamine aerosol in the scorbutic guinea-pig.

Evaluation of antihistaminic activity of Piper betel leaf in guinea pig

Piper betel Linn. leaves were evaluated for its antihistaminic activity, commonly known as Pan, Vidyache Pan or Tamboli. P. betel has a long history of use in India being applied in multiple therapeutic activities like antibacterial, treating eczema, lymphangitis, asthma, treating rheumatism. So selected, the plant P. betel is effective in histaminic activity related diseases, but antihistaminic activity of P. betel is still not scientifically investigated. In the present study, the pharmacological evaluation of ethanolic extract and essential oil extract of leaves of P. betel Linn. has been done for their antihistaminic activity on guinea pig. In isolated guinea pig tracheal chain preparation, there was a right side shift of dose response curve (DRC) of histamine. Chlorpheniramine maleate was used as a standard drug. Moreover extracts of P. beteldisturbed histamine aerosol induce bronchoconstriction in whole guinea pig, where essential oil was more effective comparatively to ethanolic extract. Thus from the results obtained in the present investigation, it can be concluded that ethanolic extract and essential oil of P. betel Linn possess antihistaminic activity. Key words: Piper betel leaf, H1-antagonist, guinea pig.

Bronchospasm potentiating effect of methanolic extract of Ficus religiosa fruits in guinea pigs

The sacred tree Peepal (Ficus religiosa family: Moraceae) has numerous therapeutic utility in folk medicine. It has been reported to be used in ethno medical treatment of asthma and also in epilepsy due to its high serotonin content, which has been implicated in pathophysiology of asthma, this led us to carry out the present study. The in vivo studies of histamine induced bronchospasm in guinea pigs and in vitro isolated guinea pig tracheal chain and ileum preparation. Pre-treatment of guinea pigs with ketotifen (1 mg/kg, p.o.) has significantly delayed the onset of histamine aerosol induced pre-convulsive dyspnea, compared with vehicle control (281.8(a)±11.7 vs. 112.2±9.8). The administration of methanolic extract (125, 250 and 500 mg/kg, p.o.) did not produced any significant effect on latency to develop histamine induced pre-convulsive dyspnea. On the other hand, methanolic extract of the fruits at the doses employed (i.e., 0.5, 1 and 2 mg/ml) has significantly potentiate the EC(50) doses of both histamine and acetylcholine in isolated guinea pig tracheal chain and ileum preparation. In addition, HPLC analysis of the methanolic extract showed the presence of high amounts of serotonin (2.89%, w/w). On the basis of data, it may be concluded that Ficus religiosa fruits have been found to be ineffective against histamine induced bronchospasm in guinea pigs. In addition, methanolic extract of the fruits have shown to potentiate the bronchoconstriction induced by both histamine and acetylcholine on guinea pig tracheal chain preparation.

Effect of parenchymal stiffness on canine airway size with lung inflation.

Although airway patency is partially maintained by parenchymal tethering, this structural support is often ignored in many discussions of asthma. However, agonists that induce smooth muscle contraction also stiffen the parenchyma, so such parenchymal stiffening may serve as a defense mechanism to prevent airway narrowing or closure. To quantify this effect, specifically how changes in parenchymal stiffness alter airway size at different levels of lung inflation, in the present study, we devised a method to separate the effect of parenchymal stiffening from that of direct airway narrowing. Six anesthetized dogs were studied under four conditions: baseline, after whole lung aerosol histamine challenge, after local airway histamine challenge, and after complete relaxation of the airways. In each of these conditions, we used High resolution Computed Tomography to measure airway size and lung volume at five different airway pressures (0, 12, 25, 32, and 45 cm H2O). Parenchymal stiffening had a protective effect on airway narrowing, a fact that may be important in the airway response to deep inspiration in asthma. When the parenchyma was stiffened by whole lung aerosol histamine challenge, at every lung volume above FRC, the airways were larger than when they were directly challenged with histamine to the same initial constriction. These results show for the first time that a stiff parenchyma per se minimizes the airway narrowing that occurs with histamine challenge at any lung volume. Thus in clinical asthma, it is not simply increased airway smooth muscle contraction, but perhaps a lack of homogeneous parenchymal stiffening that contributes to the symptomatic airway hyperresponsiveness.

Paradoxical conducting airway responses and heterogeneous regional ventilation after histamine inhalation in rabbit studied by synchrotron radiation CT

We studied both central conducting airway response and changes in the distribution of regional ventilation induced by inhaled histamine in healthy anesthetized and mechanically ventilated rabbit using a novel xenon-enhanced synchrotron radiation computed tomography (CT) imaging technique, K-edge subtraction imaging (KES). Images of specific ventilation were obtained using serial KES during xenon washin, in three axial lung slices, at baseline and twice after inhalation of histamine aerosol (50 or 125 mg/ml) in two groups of animals (n = 6 each). Histamine inhalation caused large clustered areas of poor ventilation, characterized by a drop in average specific ventilation (sV(m)), but an increase in sV(m) in the remaining lung zones indicating ventilation redistribution. Ventilation heterogeneity, estimated as coefficient of variation (CV) of sV(m) significantly increased following histamine inhalation. The area of ventilation defects and CV were significantly larger with the higher histamine dose. In conducting airways, histamine inhalation caused a heterogeneous airway response combining narrowing and dilatation in individual airways of different generations, with the probability for constriction increasing peripherally. This finding provides further in vivo evidence that airway reactivity in response to inhaled histamine is complex and that airway response may vary substantially with location within the bronchial tree.

Investigation into the mechanism of action of Moringa oleifera for its anti-asthmatic activity

In the present investigation, we studied the effect of alcoholic extract of Moringa oleifera (M. oleifera) seed kernels on various experimental models of bronchial asthma. Significant (P < 0. 05) increase in preconvulsion time was observed due to pretreatment with M. oleifera when the guinea pigs were exposed to either acetylcholine (Ach) or histamine aerosol. This bronchodilating effect of M. oleifera was comparable to ketotifen fumarate. Spasmolytic effect of M. oleifera was also observed by dose dependent inhibition of ideal contractions induced by Ach, 5HT, histamine and <TEX>$BaCl_2$</TEX>. Alcoholic extract of M. oleifera produced significant dose dependent protection by egg albumin and compound 48/80 induced mast cell degranulation. Pretreatment with alcoholic extract of M. oleifera also decreased carrageenan induced rat paw edema, which was comparable to that of standard diclofenac sodium. Minimum inhibitory concentration for alcoholic extract of M. oleifera was low as compared to cold-water extract and hot water extract when antimicrobial activity was tested against various respiratory pathogens like Escherichia coli (E. coli), Staphylococus aureus (S. aureus) and pseudomonas aeruginosa (P. aeruginosa). Our data suggest that antiasthmatic activity of M. oleifera seed kernels may be due to its bronchodilator, anti-inflammatory, mast cell stabilization and antimicrobial activity.

Area under the Maximum Expiratory Flow-Volume Curve – A Sensitive Parameter in the Evaluation of Airway Patency

Background: The most frequently used parameters for assessing bronchoconstriction and bronchodilation are forced expiratory volume in 1 s (FEV₁) and peak expiratory flow (PEF). Objectives: To assess the sensitivity of other parameters after induced bronchoconstriction and bronchodilation. Methods: From maximum expiratory flow-volume (MEFV) curves, forced vital capacity, FEV₁, PEF, maximum expiratory flows (MEF) at 25, 50 and 75% of vital capacity and the area under the MEFV curve (A_ex) were measured in two groups of asthmatic children after induced bronchoconstriction and bronchodilation, and in children with cystic fibrosis (CF) after bronchodilation. Results: In 142 asthmatics without airway obstruction, bronchoconstriction was induced by inhalation of 1% histamine aerosol. The 20% fall in A_ex compared to baseline was found in all asthmatics, while the 20 and 15% falls in FEV₁ were noted in 36 and 65% of the patients, respectively. Other parameters were less sensitive or interpretation was problematic. Another110 asthmatics with mild-moderate airway obstruction were treated with various bronchodilators. The 20% increase in A_ex was observed in all asthmatics, while the 20% increase in FEV₁ was found in only 33% of the patients and the 15% increase in FEV₁ in 51%. In 9CF children, the pattern of changes in A_ex and FEV₁ after bronchodilation was similar to that in asthmatics. Conclusions: A_ex was a sensitive and less problematic parameter in the evaluation of airway patency in comparison with FEV₁ and other parameters measured from the MEFV curve in our study patients.

Effect of TRFK-5 on Airway Responsiveness in Ovalbumin-Treated Guinea Pigs Exposed to Tobacco Smoke

Tobacco smoke (TS) exposure can induce airway hyperresponsiveness, especially in asthma. A feature of asthma is eosinophilia. We hypothesized that tobacco smoke exposure enhances eosinophil responsiveness in sensitized guinea pigs. Tobacco smoke-exposed, ovalbumin (OA)-sensitized guinea pigs were treated with TRFK-5 (1.0 mg/kg, intraperitoneal), an anti-interleukin (IL)-5 agent, or its vehicle. Guinea pigs were challenged with aerosols of OA, capsaicin, histamine, and methacholine. TRFK-5 attenuated airway responsiveness to OA but not to capsaicin, histamine, or methacholine. Bronchial alveolar lavage fluid analysis confirmed TRFK-5 attenuated airway eosinophilia in OA-treated guinea pigs. Therefore, airway responsiveness to OA is enhanced by eosinophils or IL-5 itself.

Differences in the time course of proximal and distal airway response to inhaled histamine studied by synchrotron radiation CT

We studied the kinetics of proximal and distal bronchial response to histamine aerosol in healthy anesthetized and mechanically ventilated rabbits up to 60 min after histamine administration using a novel xenon-enhanced synchrotron radiation computed tomography imaging technique. Individual proximal airway constriction was assessed by measuring the luminal cross-sectional area. Distal airway obstruction was estimated by measuring the ventilated alveolar area after inhaled xenon administration. Respiratory system conductance was assessed continuously. Proximal airway cross-sectional area decreased by 57% of the baseline value by 20 min and recovered gradually but incompletely within 60 min. The ventilated alveolar area decreased immediately after histamine inhalation by 55% of baseline value and recovered rapidly thereafter. The results indicate that the airway reaction to inhaled histamine and the subsequent recovery are significantly slower in proximal than in distal bronchi in healthy rabbit. The findings suggest that physiological reaction mechanisms to inhaled histamine in the airway walls of large and small bronchi are not similar.

Effect of Training and Rest on Respiratory Mechanical Properties in Racing Sled Dogs

Racing Alaskan sled dogs develop exercise-induced airway inflammation, similar to that reported for elite human athletes participating in cold-weather sports. These human athletes also have airway hyperresponsiveness, but airway function in sled dogs has not been measured. To compare respiratory mechanical properties in trained, rested Alaskan sled dogs with typical laboratory hounds, and to determine whether subsequent training alters respiratory mechanical properties. Nineteen healthy adult Alaskan sled dogs were compared with five healthy adult mixed-breed laboratory hounds. All dogs were rested for at least 4 months before examination. Respiratory mechanical properties were measured while the dogs were anesthetized and ventilated with a piston ventilator. The mean respiratory resistance and compliance measurements for 20 consecutive breaths were used as baseline values immediately before measurement of respiratory reactivity. Respiratory reactivity was the mean of 20 consecutive breaths immediately after the administration of aerosol histamine, expressed as the percentage change in prehistamine measurements. After the initial examinations, the sled dogs were divided into exercised and controls. Exercised dogs were trained for competitive endurance racing. Both groups were examined after 2 and 4 months of training. Alaskan sled dogs had greater respiratory compliance reactivity to histamine (77.47 +/- 8.58% baseline) compared with laboratory dogs (87.60 +/- 9.22% baseline). There was no effect of training on respiratory mechanical properties detected in racing sled dogs. Racing Alaskan sled dogs have airway dysfunction similar to "ski asthma" that persists despite having 4 months of rest. These findings suggest that repeated exercise in cold conditions can lead to airway disease that does not readily resolve with cessation of exercise.

Antihistaminic and antianaphylactic activity of HK-07, a herbal formulation

<b>Objective:</b> To study the antianaphylactic, antihistaminic and mast cell stabilization activity of HK-07 in experimental animals.<br><b> Materials and Methods:</b> HK-07 is a polyherbal formulation containing extracts of various plant constituents. The compound HK-07 was evaluated using Wistar rats and Duncan Hartley guinea pigs. The antianaphylactic activity was investigated in rats using the active anaphylaxis model. The effect on mast cell stabilization was performed by <i> ex vivo</i> challenge of antigen in sensitized rat intestinal mesenteries. Antihistaminic activity was studied in guinea pigs using histamine-induced bronchospasm where preconvulsive dyspnea was used as an end point following exposure to histamine aerosol. Dose response studies of HK-07 were conducted at 125, 250, and 500 mg/kg, p.o. in anaphylactic shock-induced bronchospasm in rats. The optimal dose level was used for the remaining experimental models. <br><b> Results:</b> Treatment with HK-07 at 125, 250, and 500 mg/kg, p.o. showed significant reduction in signs and severity of symptoms (P <0.05), onset (P <0.001) and mortality rate (P <0.05) following anaphylactic shock-induced bronchospasm. HK-07 also significantly reduced the serum IgE levels (P <0.001) in animals compared to untreated controls. Treatment of sensitized animals with HK-07 at 500 mg/kg, p.o. for 2 weeks resulted in a significant reduction in the number of disrupted mast cells (P <0.001) when challenged with an antigen (horse serum). HK-07 significantly prolonged the latent period of convulsion (P <0.008) as compared to control following exposure of guinea pigs to histamine aerosol.<b> <br>Conclusion:</b> The findings from various studies reveal that the antihistaminic and antianaphylactic activity of HK-07 may be due to the mast cell stabilizing potential, suppression of IgE, and inhibition of release of inflammatory mediators.<br>

Quantitative measurement of regional lung gas volume by synchrotron radiation computed tomography

The aim of this study was to assess the feasibility of a novel respiration-gated spiral synchrotron radiation computed tomography (SRCT) technique for direct quantification of absolute regional lung volumes, using stable xenon (Xe) gas as an inhaled indicator. Spiral SRCT with K-edge subtraction using two monochromatic x-ray beams was used to visualize and directly quantify inhaled Xe concentrations and airspace volumes in three-dimensional (3D) reconstructed lung images. Volume measurements were validated using a hollow Xe-filled phantom. Spiral images spanning 49 mm in lung height were acquired following 60 breaths of an 80% Xe–20% O2 gas mixture, in two anaesthetized and mechanically ventilated rabbits at baseline and after histamine aerosol inhalation. Volumetric images of 20 mm lung sections were obtained at functional residual capacity (FRC) and at end-inspiration. 3D images showed large patchy filling defects in peripheral airways and alveoli following histamine provocation. Local specific lung compliance was calculated based on FRC/end-inspiration images in normal lung. This study demonstrates spiral SRCT as a new technique for direct determination of regional lung volume, offering possibilities for non-invasive investigation of regional lung function and mechanics, with a uniquely high spatial resolution. An example of non-uniform volume distribution in rabbit lung following histamine inhalation is presented.

A Preliminary Study on the Effect of Azadirachta indica on Bronchial Smooth Muscles and Mast Cells

Objective : The present study was designed to assess the protective effect of Azadirachta indica on bronchial smooth muscles and mast cells. Methods : Azadirachta indica (200 mg/kg p.o.) leaf juice was administered to animals and its protective effect was determined on histamine aerosol induced bronchospasm in guinea pigs, comp 48/80 induced mast cell degranulation and active anaphylaxis in rats. Results : A significant protection against histamine induced bronchospasm in guinea pigs was observed. There was 63% delay in onset of dyspnoea in A. indica treated animals against that of 16% in control animals. A. indica neither could prevent mast cell degranulation nor could protect against active anaphylaxis. Conclusion : The results of the present preliminary study reveal that A. indica has bronchoprotective role. Moreover, it also suggests that mechanisms other than that associated with mast cell degranulation or active anaphylaxis are possibly involved in bronchoprotective role of A. indica .

Asthma and allergy: a worldwide problem of meanings and management?

Asthma and allergy: a worldwide problem of meanings and management?

Tranquilizing, antihistaminic and purgative activity of Nyctanthes arbor tristis leaf extract

The decoction of the leaves of Nyctanthes arbor tristis Linn. (Harsingar) is widely used in Ayurvedic system of medicine for the treatment of sciatica, arthritis, fevers, various painful conditions and as laxative. In the present investigation, the water soluble portion of the alcoholic extract of the leaves was screened for some CNS activities (viz. hypnotic, tranquilizing, local anaesthetic, hypothermic, anticonvulsant), antihistaminic and purgative activities. The extract produced general depression of spontaneous motor activity, significantly increased pentobarbitone sleeping time though it had no effect on righting reflex. Furthermore higher doses of the extract abolished CAR without affecting motor coordination. Moreover the extract exhibited hypothermic effect and protected guinea pigs from histamine aerosol. These activities are common to major tranquilizers and support the usage of the plant by Ayurvedic physicians in aforementioned conditions. In addition significant purgative activity was also exhibited by the extract.

Interleukin-1beta and tumour necrosis factor-alpha increase microvascular leakage in the guinea pig trachea.

Airway microvascular leakage is considered to be an important component of airway inflammation in asthma. In the present study we examined the effect of interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNFalpha) on airway microvascular leakage in vivo. Tracheal Evans blue extravasation was examined in an isolated tracheal segment, in anaesthetized mechanically ventilated guinea pigs. Baseline tracheal microvascular leakage was measured in five animals. As a control group for aerosol challenge, the isolated tracheal segment (n = 5) underwent saline aerosol challenge. To test whether a combination of IL-1beta (10 ng/mL) and TNFalpha (100 ng/mL) induced Evans blue extravasation, the trachea was exposed to an aerosol of these cytokines (n = 5). As a positive control the tracheal segment was challenged with histamine aerosol (5 x 10(-2) mol) (n = 3). All aerosol challenges were for 1 min. TNFalpha and IL-1beta aerosol challenge significantly increased Evans blue extravasation (28.9 +/- 1.6 microg/g wet tissue, mean +/- SE) compared to saline challenge (13.8 +/- 3.0 microg/g; P < 0.05). Tracheal dye extravasation without aerosol challenge, was not significantly different from saline-challenged animals (17.5 +/- 2.9 and 13.8 +/- 3.0 microg/g, respectively). Histamine significantly increased Evans blue extravasation (50.1 +/- 4.8 microg/g; P < 0.05) compared to saline challenge. Pro-inflammatory cytokines, TNFalpha and IL-1beta are able to induce significant microvascular leakage in the guinea pig trachea.

Eicosanoids modulate hyperpnea-induced late phase airway obstruction and hyperreactivity in dogs

A canine model of exercise-induced asthma was used to test the hypothesis that the development of a late phase response to hyperventilation depends on the acute production of pro-inflammatory mediators. Peripheral airway resistance, reactivity to hypocapnia and aerosol histamine, and bronchoalveolar lavage fluid (BALF) cell and eicosanoid content were measured in dogs ∼5 h after dry air challenge (DAC). DAC resulted in late phase obstruction, hyperreactivity to histamine, and neutrophilic inflammation. Both cyclooxygenase and lipoxygenase inhibitors administered in separate experiments attenuated the late phase airway obstruction and hyperreactivity to histamine. Neither drug affected the late phase inflammation nor the concentrations of eicosanoids in the BALF obtained 5 h after DAC. This study confirms that hyperventilation of peripheral airways with unconditioned air causes late phase neutrophilia, airway obstruction, and hyperreactivity. The late phase changes in airway mechanics are related to the hyperventilation-induced release of both prostaglandins and leukotrienes, and appear to be independent of the late phase infiltration of inflammatory cells.