Mechanism of cough and bronchoconstriction induced by distilled water aerosol

We studied the relationship between cough and bronchoconstriction caused by inhaled distilled water aerosol in 8 subjects with asthma by measuring specific airways resistance (SRaw) and recording cough while subjects breathed serially increasing volumes of distilled water or normal saline aerosol produced by an ultrasonic nebulizer. We performed the distilled water dose-response curves after no treatment and after treatment with cromolyn aerosol, lidocaine aerosol, or atropine aerosol in doses of 0.2 mg and 2.0 mg on separate days. Without prior treatment, distilled water aerosol caused cough in 7 of 8 subjects and a marked increase in SRaw in every subject, whereas saline aerosol did not cause cough or a greater than 50% increase in SRaw in any subject. The 2 doses of atropine caused an equivalent reduction in baseline SRaw, but 2.0 mg caused greater inhibition of water-induced bronchoconstriction than did 0.2 mg. Neither dose of atropine inhibited cough. These data suggest that water-induced bronchoconstriction involves cholinergic nerves and that water-induced cough is not dependent on bronchoconstriction. Lidocaine inhibited cough but not bronchoconstriction, whereas cromolyn inhibited bronchoconstriction but not cough, suggesting that cromolyn does not inhibit bronchoconstriction by a generalized inhibition of airway afferent nerves.     

Serial distribution of bronchoconstriction in normal subjects. Methacholine versus histamine

We compared the relative sites of airway responses to methacholine and histamine aerosols in normal subjects by simultaneous assessment of respiratory resistance (Rrs) and anatomic dead space (VD). Methacholine (12.5 mg/ml) or histamine (12.5 mg/ml) was continuously inhaled during tidal breathing until a nearly twofold increase in Rrs was observed. Large airway response was determined by VD, and overall airway response was determined by Rrs. Small airways response was inferred from Rrs when the change in VD was slight. Inhalation of methacholine and histamine increased Rrs with decreased VD, but the decrease in VD was significantly greater with methacholine than with histamine for an equivalent change in Rrs (p less than 0.01). Inhalation of atropine (5 mg/ml) decreased Rrs with a simultaneous increase in VD. After inhalation of atropine, time required for a twofold increase in Rrs by histamine inhalation was prolonged, and histamine did little decrease VD. These results suggest that the predominant site of cholinergically mediated constriction is the large airways, and that histamine constricts the large airways in part via a cholinergic reflex mechanism and constricts the small airways via its direct action in normal subjects.     

Hypoxia enhances nonspecific bronchial reactivity

Enhancement of nonspecific bronchial reactivity has been observed after antigen-induced bronchoconstriction, a mast-cell-mediated phenomenon. Because hypoxia also causes degranulation of mast cells, we tested the hypothesis that alveolar hypoxia produces nonspecific bronchial reactivity. In 11 conscious sheep, we determined specific lung resistance (SRL) (mean pulmonary flow resistance times thoracic gas volume) before and after exposure to either air-sham or a hypoxic gas mixture (13% O2, balance N2), with and without cromolyn sodium pretreatment. The sheep then received 50 breaths of 5% histamine or 10 breaths of 2.5% carbachol on different days. Inhalation of histamine and carbachol after air-sham caused a significant increase in mean SRL to 350 and 403% of baseline, respectively (p less than 0.01). A 30-min exposure to the hypoxic gas mixture, which per se had no effect on SRL, enhanced the histamine and carbachol-induced increases in SRL to 519 and 472% of baseline (p less than 0.01). These increases were significantly greater than those observed after air-sham exposure (p less than 0.05). Infusion of cromylyn sodium (3 mg/kg/min) before and during exposure to hypoxia prevented the posthypoxia enhancement of histamine-induced (n = 7) and carbachol-induced (n = 5) bronchoconstriction, without affecting the airway responsiveness to these agents during normoxia. These data suggest that alveolar hypoxia enhances nonspecific bronchial reactivity in sheep, which may be related to hypoxia-induced release of mast-cell mediators.     

Airway hyperreactivity in patients undergoing lung and heart/lung transplantation

To assess airway reactivity in lung transplant patients, three heart/lung, three double lung, and eight single lung transplant patients underwent airway challenge tests. All patients were assessed by methacholine aerosol challenge and thirteen were also assessed by histamine aerosol challenge at least three months after transplant surgery. The airways of patients with bilaterally denervated lungs (heart/lung and double lung transplants) were significantly more reactive to both methacholine and histamine (p less than 0.01) than were the airways of patients with unilaterally denervated (single lung transplants) lungs. Inflammatory changes in the airway mucosal biopsies were minimal in three patients and absent in all others. These studies raise questions about the role of central innervation in the maintenance of normal airway function as well as the mechanisms of action of both methacholine and histamine in causing bronchoconstriction.     

Histamine bronchoconstriction reduces airway responsiveness in asthmatic subjects

Tachyphylaxis occurs to repeated challenges with inhaled histamine but not with inhaled acetylcholine in asthmatic subjects. This study was undertaken to determine whether prior histamine bronchoconstriction reduces airway responsiveness to inhaled acetylcholine in mild asthmatic subjects demonstrating histamine tachyphylaxis. All subjects developed histamine tachyphylaxis with repeated histamine challenge. The mean histamine PC20 increased from 3.74 to 5.92 mg/ml (p less than 0.005) when the histamine challenges were separated by 1 h. Prior acetylcholine bronchoconstriction did not reduce airway responsiveness to subsequent inhalation of either acetylcholine or histamine in these subjects. However, histamine inhalation did reduce airway responsiveness to acetylcholine in all subjects. The mean acetylcholine PC20 following acetylcholine inhalation was 3.37 mg/ml (%SD 2.17) and this increased to 7.76 mg/ml (%SD 1.80) after histamine inhalation (p less than 0.0005). Thus, this study demonstrates that prior histamine, but not acetylcholine, bronchoconstriction can partially protect against bronchoconstriction caused by both histamine and acetylcholine. Therefore, reduced airway responsiveness caused by histamine bronchoconstriction is specific for histamine and is not due to bronchoconstriction per se. However, the reduced airway responsiveness following histamine bronchoconstriction, is nonspecific.     

Effects of ammonia and histamine on lung irritant receptors in the rabbit

The effects of ammonia and histamine on the responses of rapidly adapting pulmonary stretch receptor (RAR) activity before and after administration of isoprenaline or atropine were studied in spontaneously breathing rabbits. Inhalation of vapor from 15% ammonia solution increased the activity of RARs and this increased activity was not significantly altered by isoprenaline (50 micrograms/kg) or atropine (0.3 mg/kg). The RARs increased their activity following intravenous injections of histamine (20, 40 and 60 micrograms/kg). The excitatory responses to histamine at different doses were blocked by prior treatment with isoprenaline (50 micrograms/kg). In 8 of the tested 11 different RAR preparations on 11 rabbits, atropine (0.3 mg/kg) greatly diminished the increases of RAR activity produced by histamine at different doses. These results suggest that the ammonia-induced RAR stimulation results in a direct action of the endings whereas the activation of RARs by histamine is probably due to the combined influence of both local airway constriction and postganglionic parasympathetic pathway-mediated bronchoconstriction.     

Bronchial hyperresponsiveness in normal subjects during attenuated influenza virus infection

Fourteen healthy male subjects with hemagglutination-inhibition antibody titers of 1:8 or less to homologous influenza A virus were studied. Six subjects received live, attenuated influenza virus by nasal drops and by aerosol. Although infection occurred in these six subjects, with the development of 4-fold or greater increases in hemagglutination-inhibition antibody titers, they remained asymptomatic. Eight subjects received placebo via the same route, and did not develop symptoms and showed no increase in antibody titer. Prior to administration of virus or placebo, histamine diphosphate aerosol increased airway resistance only slightly, and there was no difference between the virus and placebo groups. Two days after inoculation, bronchomotor responses in the placebo group were unchanged (p greater than 0.05), but in the virus-infected group, bronchomotor responses were significantly greater than in the preinfected state (p less than 0.01). Isoproterenol hydrochloride reversed and prevented the increase in airway resistance after histamine, suggesting that the bronchoconstriction was caused by smooth muscle contraction. Our findings indicate that transient, asymptomatic respiratory virus infection augments airway smooth muscle responses.     

Modulation of the bronchomotor effects of chemical mediators by prostaglandin F2 alpha in asthmatic subjects

Prostaglandin F2 alpha (PGF2 alpha) is generated by human lung tissue in response to a number of stimuli and is widely viewed as a bronchoconstrictor mediator. We have shown that aerosolized PGF2 alpha in concentrations between 1 and 100 micrograms/ml caused dose-related bronchoconstriction, but that continued stimulation at higher concentrations resulted in a partial return of pulmonary function toward control, suggesting that airways were refractory to further stimulation. To explore the mechanism and specificity of airway refractoriness induced by PGF2 alpha, we examined bronchomotor responses evoked by repeated PGF2 alpha stimulation, repeated histamine stimulation, and PGF2 alpha stimulation followed by histamine. Studies were carried out on 3 separate days in 7 subjects with allergic asthma. For each subject the aerosol concentration of each agonist remained constant throughout the study. Responses were measured as the percent change in FEV1 versus time, and comparisons were made between the first and second agonist challenge of each study day. We found that prior stimulation with PGF2 alpha resulted in diminished airway responsiveness, not only to PGF2 alpha but to histamine as well. In contrast, similar refractoriness could not be induced by repeated histamine stimulation, indicating that the PGF2 alpha-induced decrease in responsiveness was not a nonspecific effect of bronchoconstriction per se. Further, the finding that PGF2 alpha caused a decrease in the response to histamine suggests that diminished airway responsiveness was not due to down-regulation of specific PGF2 alpha receptors. Our findings suggest that in addition to its bronchoconstrictor properties, PGF2 alpha may play a role in the modulation of acute airway responses.     

Regional deposition of particles in human lung after induced bronchoconstriction

The percentage 24-hr lung retention (Ret24), a measure of penetration to the aveoli, of 4 micron monodispersed Teflon particles, aerodynamic diameter 6 micron, was studied in 8 healthy nonsmokers. The particles were inhaled at 0.2 1/sec with maximally deep breaths. Bronchoconstriction was induced by inhalation of a methacholinebromide aerosol for one exposure before and for one exposure after inhalation of the Teflon particles. Airway resistance (Raw) was measured using a whole body pletysmograph before and after the induction of bronchoconstriction and increased on an average by a factor 2-3. Ret24 was significantly lower when the Teflon particles were inhaled during bronchoconstriction than when bronchoconstriction was induced after inhalation of the Teflon particles, 26 +/- 12% and 48 +/- 6% (mean +/- SD), respectively. These experimental data agree fairly well with data on deposition due to impaction and sedimentation using a lung model where the diameters of the airways were varied so that an increase in airway resistance occurs similar to that produced in our experimental subjects. However, the experimental data tended to be lower than the theoretical ones when the particles were inhaled during the induced bronchoconstriction. In this study, where the mucociliary transport system was stimulated by methacholinebromide, the percentage 3-hr retention (Ret3) was highly correlated with Ret24, r = 0.97, i.e., Ret3 can be used instead of the Ret24. This implies that radionuclides with shorter half-lives which give lower radiation doses, can be used, and that subjects can be studied within shorter periods of time.     

Role of nitric oxide released from iNANC neurons in airway responsiveness in cats.

The precise role of inhibitory nonadrenergic noncholinergic (iNANC) neurons and nitric oxide in airway hyperresponsiveness remains uncertain. The role of NO in the regulation of airway responsiveness was studied in anaesthetized and mechanically ventilated cats. To assess airway responsiveness, the changes in total pulmonary resistance (RL) produced by delivering serotonin aerosol to the airways were measured before and after N(omega)-nitro-L-arginine methyl ester (L-NAME), or a ganglionic blocker, hexamethonium, which has been reported to block iNANC. Serotonin was chosen because it causes bronchoconstriction in part by neural reflex. To further clarify the mechanism(s) involved, the effect of inhaled capsaicin was also determined in animals with sustained bronchoconstriction induced by serotonin after treatment with atropine and propranolol. Inhibition of NO synthase by L-NAME or blockade of iNANC neurons by hexamethonium significantly increased airway responsiveness. However, addition of L-NAME did not further increase airway responsiveness in animals treated with hexamethonium. In the presence of atropine and propranolol, inhaled capsaicin caused a marked bronchodilation during serotonin-induced sustained bronchoconstriction. The bronchodilation induced by capsaicin was significantly suppressed by hexamethonium and by L-NAME. These results suggest that the nitric oxide released from inhibitory nonadrenergic noncholinergic neurons is important in modulating the airway responsiveness of cats in vivo.     

Airway resistance and deposition of particles in the lung

The percentage 24-h lung retention of 4-micrometers monodispersed Teflon particles, aerodynamic diameter about 6 micrometers, was studied twice in 8 healthy nonsmokers. The particles were inhaled at 0.5 liter/sec with maximally deep breaths. Bronchoconstriction was induced by inhalation of a methacholine-bromide aerosol for one exposure before and for the other 20-30 min after the inhalation of the Teflon particles. For both exposures, airway resistance (Raw) was measured with a whole body plethysmograph before and after the induction of the bronchoconstriction and was found on an average to increase with a factor of 2-3. For the exposure when bronchoconstriction was induced after the inhalation of the Teflon particles, Raw and 24-h lung retention correlated significantly. Retention at 24 h was markedly lower when bronchoconstriction was induced before inhalation of the Teflon particles than when bronchoconstriction was induced after, the ranges being 13-24% and 38-68%, respectively. The experimental data agreed well with theoretical data from a lung model wherein the diameters of the airways were varied. The results indicate that the magnitude of bronchoconstriction occurring in real life can protect the alveolar part of the lung by reducing the amount of inhaled particles that deposit there.     

Interpretation of cough provoked by airway challenges

STUDY OBJECTIVE: To analyze the cough response to three airway challenges in order to clarify whether the recording of the provoked coughs would be beneficial in the management of asthma. DESIGN: A prospective study. SETTING: University hospital. PARTICIPANTS: Fifteen healthy subjects, 16 steroid-na?ve subjects with asthma, and 16 subjects with steroid-treated asthma. INTERVENTIONS: Inhalation challenges with isotonic histamine, hypertonic saline solution, and hypertonic histamine, using an ultrasonic nebulizer and 2-min tidal breathing method. MEASUREMENTS: Airflow parameters were measured with a spirometer, and the coughs were recorded manually. RESULTS: Coughing during the isotonic histamine challenge was associated with the degree of the bronchoconstriction induced. When this was taken into account, the healthy subjects coughed as frequently as the asthmatic subjects. During the two hypertonic challenges, the asthmatic subjects coughed more frequently than did the healthy subjects when the induced bronchoconstriction had not yet developed. At that stage of the hypertonic saline solution challenge, the mean coughing frequency was 0.7 coughs per minute (95% confidence interval [CI], 0.03 to 1.3 coughs per minute) for the healthy subjects, 2.7 coughs per minute (95% CI, 0.8 to 4.5 coughs per minute) for the steroid-na?ve asthmatic subjects, and 1.3 coughs per minute (95% CI, 0.6 to 1.9 coughs per minute) for the steroid-treated asthmatic subjects (p = 0.018). For the hypertonic histamine challenge, the respective values were 0.8 coughs per minute (95% CI, 0.4 to 1.2 coughs per minute), 3.6 coughs per minute (95% CI, 2.4 to 4.9 coughs per minute), and 2.1 coughs per minute (95% CI, 1.0 to 3.1 coughs per minute; p = 0.001). This cough did not correlate with airway hyperresponsiveness. CONCLUSIONS: Coughing during isotonic histamine challenge seems to be a manifestation of bronchoconstriction, and recording of the coughs may not provide additional information to airflow measurements. Frequent coughing during hypertonic saline solution and hypertonic histamine challenges in the absence of bronchoconstriction is a pathologic phenomenon. Sensitivity to the cough-provoking effect of hypertonic challenges seems to be enhanced in patients with asthma but unrelated to airway hyperresponsiveness. Therefore, the recording of the provoked coughs during these challenges may add to the information obtained from airflow measurements.     

Effect of nifedipine on dose-response curves to acetylcholine and histamine measured during quiet breathing

We have investigated the effect of nifedipine on acetylcholine-induced bronchoconstriction in 8 asthmatics and on histamine-induced bronchoconstriction in another 8 asthmatics on a single-blind basis. Expiratory spirograms were done at the beginning of the examination in all subjects, and repeated after 10 mg of oral nifedipine or a placebo. The change of respiratory resistance during the inhalation of acetylcholine or histamine was recorded continuously by an Astograph. Using this device, we were able to obtain the direct-writing dose-response curve of respiratory resistance measured during quiet breathing. Resting airway tone appeared to be generally unaffected by nifedipine, as there was no significant change in baseline spirograms. Nifedipine increased significantly the threshold of bronchial responsiveness, i.e., the cumulative dose of acetylcholine (Dmin) at which the respiratory resistance started to increase, compared with placebo (p less than 0.02). However, Sd, the slope of the increasing rate of respiratory resistance in the dose-response curve, was not attenuated by nifedipine. In histamine inhalation tests, neither Dmin nor Sd were modified by nifedipine. The discrepancy observed between the effects of nifedipine on acetylcholine- and histamine-induced bronchoconstriction may imply that, in asthmatics, nifedipine exerts its effect mainly by stabilizing mast cells rather than by directly inhibiting bronchial smooth muscle contractility. This hypothesis is based on the fact that mast cells have acetylcholine receptors on their surfaces but no histamine H1-receptors.     

Airway responsiveness to histamine and leukotriene E4 in subjects with aspirin-induced asthma

Airway responsiveness to histamine and leukotriene E4 (LTE4) has been compared between five subjects with aspirin-induced asthma (AIA) and 15 asthmatic subjects without aspirin sensitivity (non-AIA). In the AIA group, the geometric mean doses of histamine and LTE4 causing a 35% fall in specific airway conductance (PD35) were 0.31 mumol and 0.17 nmol, respectively, and LTE4 was 1,870 times more potent than histamine. In the non-AIA group, the histamine and LTE4 PD35 doses were 0.40 mumol (non-AIA versus AIA, NS) and 2.8 nmol (non-AIA versus AIA, p = 0.002), respectively, and LTE4 was 145 times more potent than histamine in eliciting bronchoconstriction (non-AIA versus AIA, p = 0.001). After desensitization to aspirin the geometric mean histamine and LTE4 PD 35 in the AIA group changed to 0.19 mumol (NS) and 3.3 nmol (p = 0.007), respectively, and there was an average 33-fold reduction in the responsiveness of the airways to LTE4 relative to histamine (p less than 0.001). In five non-AIA subjects. Ingestion of 600 mg of aspirin daily did not lead to any significant change in airway responsiveness to histamine or to LTE4. These results demonstrate a selective and marked increase in airway responsiveness to LTE4 in subjects with AIA. The efficacy of desensitization may relate in part to a selective down-regulation of LTE4 receptors within the airways.     

Mechanism of platelet activating factor-induced bronchoconstriction in humans

The inhalation of platelet activating factor (PAF) produces bronchoconstriction in normal and asthmatic subjects. To identify the mechanism by which PAF-induced bronchoconstriction occurs in humans, bronchoprovocation testing was performed in 7 subjects (3 normal, 4 with mild asthma) after pretreatment with phosphate-buffered saline (PBS), atropine, chlorpheniramine, or indomethacin. We determined the nebulizer concentration of PAF which reduced specific airway conductance (SGaw) 35% (PC35 SGaw) and the slope of the PAF dose-response curve. Atropine produced baseline bronchodilatation (SGaw increased 50%), while chlorpheniramine and indomethacin had no effect on baseline pulmonary function. Atropine increased airway responsiveness to PAF: the PC35 SGaw decreased 40% (p less than 0.05) and the slope of the PAF dose-response curve increased 86% (p less than 0.05). In contrast, chlorpheniramine inhibited the airway response to PAF: the PC35 SGaw increased 87% (p less than 0.05), while the slope of the PAF dose-response curve decreased an insignificant 37%. Indomethacin did not affect either measurement. Chlorpheniramine also prevented the PAF-induced facial flushing and feeling of warmth; atropine and indomethacin did not. These results suggest that PAF-induced bronchoconstriction in humans is mediated at least in part by histamine release, not by cholinergic or cyclooxygenase-dependent mechanisms. Other indirect effects, such as the release of sulfidopeptide leukotrienes, or a direct effect on airway smooth muscle may also contribute to PAF-induced bronchoconstriction. Why atropine heightened the airway response to PAF is unclear.     

In vivo measurements of airway reactivity using high-resolution computed tomography

Changes in airway resistance are reported to account for only a portion of changes in total lung resistance. The fraction of total lung resistance caused by airway resistance is difficult to quantify in vivo. High-resolution computed tomography (HRCT) has potential application for directly measuring changes in airway size in vivo. In the present investigation, we studied five anesthetized mongrel dogs using HRCT to locate and measure changes in airway area after aerosol histamine challenge in the absence and presence of deep inspiration. We also related changes in total lung resistance to changes in airway area. We found that in all dogs after histamine aerosol challenge, airway area decreased (range, 23 +/- 7 to 67 +/- 5%, mean +/- SEM), and total lung resistance increased (range, 191 to 378%). After deep inspiration (equal to three times tidal volume), four of the five dogs showed further significant decreases in airway area (range, 13 +/- 6 to 71 +/- 8%), whereas all five dogs showed decreases in RL (range, 3 to 35%). The fact that preconstricted airways constricted further after deep inspiration while the measured RL decreased suggests that RL may not always be a reliable indicator of changes in the size of conducting airways larger than 1 mm.     

The influence of refractoriness to adenosine 5'-monophosphate on allergen-provoked bronchoconstriction in asthma

Repeated bronchoprovocation with adenosine 5'-monophosphate (AMP) in atopic, nonasthmatic subjects produces a state of refractoriness to the nucleotide that may be due either to depletion of preformed mediators from airway mast cells or down-regulation of purinoceptors on the surface of these cells. To investigate this further, we compared the effect on immediate allergen-provoked bronchoconstriction of preceding repeated challenges with histamine and AMP in eight atopic, mildly asthmatic subjects. In three successive AMP concentration-response studies, the geometric mean PC20 AMP increased from 275.3 to 1154.3 (p less than 0.01) and 1976.7 (p less than 0.01) mg/ml, respectively, whereas no significant similar increase in PC20 occurred with repeated histamine challenges. Refractoriness to AMP was not associated with any significant decrease in airways responsiveness to histamine. When compared with the response after repeated provocation with inhaled histamine, repeated exposure of the airways to AMP potentiated, rather than inhibited, immediate allergen-induced bronchoconstriction by a mean 57 +/- 22.6% (p less than 0.05) when the data were expressed as the area under the FEV1-time response curve. The ability of airways that have been rendered less responsive to inhaled AMP to exhibit an increased response to allergen suggests that tachyphylaxis to AMP is unlikely to be caused by depletion of preformed mast cell-derived mediators such as histamine.     

Enhanced aerosol deposition in the lung with mild airways obstruction

We investigated the sensitivity of aerosol deposition to airways obstruction by measuring total deposition fraction of inert aerosol in normal conscious sheep (n = 6) after challenging cholinergic agent, pilocarpine (PL) (0.5 mg/kg intravenously) with and without a prior challenge of beta 2-adrenergic agonist, terbutaline sulfate (TS) (0.025 mg/kg subcutaneously). Aerosol deposition was measured by a light-scattering aerosol photometer in situ while sheep rebreathed 1.0-micron-diameter inert oil droplets from a 0.2-L collapsible bag at a rate of 30 breaths/min. Total accumulated deposition at the fifth breath (AD5) as a percentage of initial aerosol concentration was determined and compared with mean pulmonary airflow resistance (RL). After PL, both AD5 and RL increased significantly from baseline values by 51 +/- 9% and 597 +/- 118% (mean +/- SE), respectively, whereas AD5 and RL decreased significantly by 16 +/- 4% and 34 +/- 6%, respectively after TS (p less than 0.05). After PL subsequent to TS (TS-PL), AD5 increased in all six sheep by 33 +/- 7% from post-TS values (p less than 0.05). However, RL did not change from post-TS values. Greater changes in RL than in AD5 after PL (bronchoconstriction) or TS (bronchodilation) suggest a greater sensitivity of RL than AD5 to airway patency in the large airways. Lack of increase of RL after TS-PL indicates that bronchoconstrictive effect of PL was blocked by prior challenge with TS. Therefore, the increase in AD5 after TS-PL may be related to the peripheral airway obstructions which might have been caused by increased secretions induced by a potent secretagogue PL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined lidocaine and salbutamol inhalation for airway anesthesia markedly protects against reflex bronchoconstriction

BACKGROUND: Lidocaine inhalation, in subjects with bronchial hyperreactivity, attenuates evoked bronchoconstriction but also irritates airways. Whether salbutamol pretreatment can mitigate airway irritation and whether combined treatment offers more protection than treatment with either drug alone is unknown. Therefore, we evaluated the effects of the inhalation of lidocaine, salbutamol, lidocaine and salbutamol combined, and placebo on an inhalational histamine challenge. METHODS: Fifteen patients with mild asthma were selected by a screening procedure (ie, a provocative concentration of a substance [histamine aerosol of < 18 mg/mL] causing a 20% fall in FEV(1) [PC(20)]). On 4 different days after pretreatment with the inhalation of lidocaine (5 mg/kg), inhalation of salbutamol (1.5 mg), combined treatment, or placebo, the histamine challenge was repeated. RESULTS: The baseline FEV(1) after lidocaine inhalation but prior to the histamine challenge decreased by > 5% in 7 of 15 volunteers, with a mean (+/- SD) decrease from 3.82 +/- 0.90 to 3.54 +/- 0.86 L (p = 0.0054). The baseline PC(20) for histamine was 6.4 +/- 4.3 mg/mL. Both lidocaine and salbutamol inhalation significantly increased PC(20) more than twofold (14.9 +/- 13.7 and 16.8 +/- 10.9 mg/mL, respectively; p = 0, 0007) at a lidocaine plasma concentration of 0.7 +/- 0.3 microg/mL. Combined treatment quadrupled the PC(20) to 29.7 +/- 20.3 mg/mL (vs lidocaine, p = 0.002; vs salbutamol, p = 0.003). CONCLUSIONS: Thus, histamine-evoked bronchoconstriction, as a model of reflex bronchoconstriction, can be significantly attenuated by salbutamol or lidocaine inhalation. However, lidocaine inhalation causes significant initial bronchoconstriction. The combined inhalation of salbutamol and lidocaine prevents the initial bronchoconstriction observed with lidocaine alone and offers even more protection to a histamine challenge than either lidocaine or salbutamol alone. Therefore, the combined inhalation of lidocaine and salbutamol can be recommended to mitigate bronchoconstriction when airway instrumentation is required.     

Leukotriene D4 (LTD4) induces mucus secretion from goblet cells in the guinea pig respiratory epithelium

To study the potential role of leukotriene (LTD4) as a mucus secretagogue, anesthetized and spontaneously breathing guinea pigs were intubated and challenged with various concentrations of an LTD4 aerosol. The resulting changes in airway resistance and compliance were then observed for 20 min, after which the animals were euthanized and the lower respiratory tract airways fixed for morphometric evaluation. Sections for these airways were stained with alcian blue-periodic acid Schiff (AB-PAS), photographed, and the content of AB-PAS positive granules in the epithelium of the extrapulmonary bronchi quantified. The fractional volume of mucus granules in the respiratory epithelial volume. Aerosol LTD4 produced a dose-dependent decrease in the granule fractional volume (GFV) over the range of 0.1 to 1 microgram/ml when compared with epithelia challenged with saline aerosols. Increasing the concentration of administered LTD4 from 1 microgram to 3 micrograms/ml produced further bronchoconstriction but had no further effect on the GFV. Decreases in GFV did not appear to be secondary to smooth muscle contraction since aerosols of other agonists (0.05% histamine and 1% acetylcholine), which yielded resistance changes similar to those of LTD4, did not effect the GFV. Pretreatment with an aerosol of the specific LTD4 receptor antagonist SK&F 104353-Z2 produced a dose-dependent inhibition of the changes in both the airway resistance and GFV. The data suggest that LTD4 mediates epithelial mucus secretion as well as bronchoconstriction in the guinea pig airway and may provide an additional therapeutic use for specific LTD4 receptor antagonists in the treatment of obstructive pulmonary disease.