Airway hyperresponsiveness to cigarette smoke in ovalbumin-sensitized guinea pigs

This study was carried out to determine if the bronchoconstrictive effect of cigarette smoke (CS) is enhanced when airway hyperresponsiveness is induced by ovalbumin (Ova) sensitization, and if so, whether an increase in endogenously released tachykinins is involved. The bronchoconstrictive effects of an acute CS inhalation challenge (15 ml; 50% concentration) were compared between guinea pigs sensitized with aerosolized Ova and matching control animals (receiving saline aerosol). In Ova-sensitized animals, there were marked increases in the numbers of eosinophils and neutrophils in the bronchoalveolar lavage fluid (BALF), which was accompanied by an elevated bronchomotor response to acetylcholine (ACh). The baseline lung resistance (RL) and dynamic pulmonary compliance (Cdyn) were not significantly different between the two groups; however, the same CS inhalation challenge evoked a significantly more intense bronchoconstriction in the Ova-sensitized group (control group: DeltaRL = 68 +/- 8%, DeltaCdyn = -26 +/- 6%; Ova group: DeltaRL = 425 +/- 76%; DeltaCdyn = -47 +/- 8%). The levels of substance P-like immunoreactivity (SP-LI) and calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) measured in the bronchoalveolar lavage (BAL) collected after CS inhalation challenge were also significantly greater in Ova-sensitized animals than in control animals. Furthermore, pretreatment with SR-48968, a selective antagonist of neurokinin-2 (NK(2)) receptor, inhibited more than 85% of the enhanced bronchomotor responses to CS challenge, but did not significantly reduce the airway hyperresponsiveness to ACh in Ova-sensitized guinea pigs. These results show that Ova sensitization induces airway hyperresponsiveness to inhaled CS, and that the endogenous tachykinins evoked by CS-induced activation of lung C fibers play a primary role in this augmented response.     

A tachykinin receptor antagonist inhibits and an inhibitor of tachykinin metabolism potentiates toluene diisocyanate-induced airway hyperresponsiveness in guinea pigs

We have previously shown that tachykinin depletion or antagonism prevented the increase in airway responsiveness to inhaled acetylcholine caused by exposure to toluene diisocyanate (TDI) in awake guinea pigs. To insure that the effects of tachykinins were not limited to the extrathoracic airways and were not dependent on effects of TDI on baseline airway caliber, we determined airway responsiveness to acetylcholine inhaled through a tracheostomy in anesthetized and ventilated guinea pigs that were exposed to TDI or air after treatment with the tachykinin antagonist spantide, the tachykinin metabolism inhibitor phosphoramidon, or the vehicles for each drug. When these drugs were administered before and during TDI exposure, spantide significantly inhibited the TDI-induced increase in acetylcholine responsiveness and phosphoramidon significantly potentiated this effect, whereas neither drug altered acetylcholine responsiveness in air-exposed animals. To determine whether tachykinins were exerting their effect primarily during TDI exposure or during the subsequent acetylcholine challenge, we also examined the effect of each drug on acetylcholine responsiveness when the drugs were given after TDI exposure. At that time, spantide did not inhibit TDI-induced acetylcholine hyperresponsiveness and phosphoramidon did not potentiate it. Neither drug nor TDI increased pulmonary resistance measured through a tracheostomy in these anesthetized and ventilated animals. These results suggest that the TDI-induced increase in acetylcholine responsiveness is mediated by release of tachykinins into the intrathoracic airways during exposure to TDI.     

Combined effects of ozone and cigarette smoke on airway responsiveness and vascular permeability in guinea pigs

The effects of combined exposure to ozone and cigarette smoke on airway responsiveness and tracheal vascular permeability, compared with those of single exposure were examined in guinea pigs. Airway responsiveness was assessed by measuring the specific airway resistance (sRaw) as a function of increasing concentration of inhaled methacholine aerosol immediately, 5 hr, and 24 hr after exposure. In a parallel study, tracheal vascular permeability was quantified by measuring the tracheal extravasation of intravenously administered Evans blue dye. Neither exposure to 1 ppm ozone for 30 min nor 5 puffs of cigarette smoke increased airway responsiveness or vascular permeability at any time after exposure. Combined exposure to 1 ppm ozone for 30 min and 5 puffs of cigarette smoke caused airway hyperresponsiveness and increased vascular permeability immediately after exposure. Exposure to 1 ppm ozone for 90 min increased both airway responsiveness and vascular permeability immediately after exposure. Exposure to 10 puffs of cigarette smoke increased airway responsiveness but not vascular permeability immediately after exposure. Combined exposure to 1 ppm ozone for 90 min and 10 puffs of cigarette smoke increased both airway responsiveness and vascular permeability immediately after exposure. The combined exposure to ozone and cigarette smoke thus increased both airway responsiveness and tracheal vascular permeability to a greater extent than did exposure to a single agent, suggesting that a combination of air pollutants has a more deleterious effect both on airway responsiveness and on tracheal vascular permeability than does either agent alone in guinea pigs. Offprint requests to: T. Okubo     

Contribution of upper airways to antigen-induced late airway obstructive responses in guinea pigs

The pathogenesis of the late asthmatic response has been of interest due to the fact that its development has been associated with airway obstruction, airway inflammation, and airway hyperresponsiveness: all features of chronic asthma. In order to study more precisely late responses, a number of animal models have been developed. Previous reports have described alterations in airway mechanics at both 3 to 6 and 17 h after antigen challenge in sensitized guinea pigs. In these experiments, however, animals were challenged through the nose with aerosolized antigen, and airway conductance was measured using whole body plethysmography while the animals breathed through the upper airways. In rats similarly challenged, the predominant immediate change in resistance occurs in the upper airways. The purpose of this study, therefore, was to evaluate the contribution made by both the upper and lower airways to late changes after allergen challenge in guinea pigs. Outbred female Hartley guinea pigs were actively or passively sensitized (IgG1 antibody response) to three different antigens and challenged either by direct tracheal insufflation (sheep gamma globulin [SGG] or oxazolone-human serum albumin [OX-HSA]) or by aerosolization (ovalbumin [OA]). Lung resistance (RL) and dynamic compliance (Cdyn) were measured in anesthetized guinea pigs through a tracheostomy tube, and specific airway conductance (SGaw) was measured in unanesthetized, nose-breathing guinea pigs using a whole body plethysmograph. Late responses were defined as a RL greater than the mean + 2 SD RL or as a decrease in SGaw from baseline greater than 2 SD from the placebo-challenged (bovine serum albumin) group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Smoking on Cough Reflex Sensitivity: Basic and Preclinical Studies

In healthy nonsmokers, inhalation of one single puff of cigarette smoke immediately evoked airway irritation and cough, which were either prevented or markedly diminished after premedication with hexamethonium. Single-fiber recording experiments performed in anesthetized animals showed that both C fibers and rapidly adapting receptors in the lungs and airways were stimulated by inhalation of one breath of cigarette smoke. Application of nicotine evoked an inward current and triggered depolarization and action potentials in a concentration-dependent manner in a subset of isolated vagal pulmonary sensory neurons. Taken together, these studies showed that activation of the nicotinic acetylcholine receptors expressed on airway sensory nerves is mainly responsible for the acute airway irritation and cough reflex elicited by inhaled cigarette smoke. Chronic exposure to cigarette smoke consistently induces enhanced cough responses to various inhaled tussive agents in guinea pigs. The increased cough sensitivity involves primarily an elevated sensitivity of cough sensors and also an enhanced synaptic transmission of their afferent signals at the nucleus tractus solitaries. In contrast to the observations in animal studies, both enhanced and diminished cough sensitivities to tussive agents have been reported in chronic smokers. This discrepancy is probably related to the history of chronic smoking of the individual smokers and the severity of existing airway inflammation and dysfunction. Furthermore, several other factors possibly contributing to the regulation of cough receptor sensitivity in chronic smokers should also be considered.     

Indomethacin potentiates the pulmonary response to aerosol leukotriene C4 in the guinea pig

Aerosol administration of leukotriene (LT) C4 to anesthetized, mechanically ventilated guinea pigs results in significant dose-dependent decrements in dynamic compliance (Cdyn) and pulmonary conductance (GL) when the concentration of LTC4 in the nebulizer is in the range of 0.5 to 5 micrograms/ml. Pretreatment with indomethacin, 30 mg/kg given intraperitoneally, significantly potentiates the decrements in Cdyn and GL elicited by aerosol LTC4 at 1 microgram/ml. Potentiation of the pulmonary response is seen even with an aerosol LTC4 concentration of 0.3 micrograms/ml, which alone produces only minimal changes in pulmonary mechanics in control animals. These findings suggest that bronchodilator prostaglandins are important inhibitory modulators of this pulmonary response and that secondary thromboxane release probably does not contribute to the response to inhaled LTC4. The effect of indomethacin pretreatment in augmenting the pulmonary response to aerosol LTC4 in the guinea pig may have relevance for the phenomenon of asthma induced in humans by ingestion of nonsteroidal anti-inflammatory agents.     

Phosphoramidon potentiates the increase in lung resistance mediated by tachykinins in guinea pigs

This study was designed to evaluate the role of endogenous enkephalinase in regulating bronchoconstrictor responses in guinea pigs. We evaluated the effects of phosphoramidon, an enkephalinase inhibitor, on the increases in lung resistance (RL) caused by exogenous substance P and inhaled capsaicin (an agent thought to provoke bronchoconstriction in guinea pigs by stimulating the release of tachykinins from afferent nerve endings). In 6 of 6 animals, phosphoramidon potentiated the substance P-induced increase in RL (RL increased 380 +/- 100% [mean +/- SEM] before phosphoramidon and 1,300 +/- 400% afterward, p less than 0.025). In 4 of 4 animals, the repeated administration of a single dose of substance P after saline did not result in potentiation of the increase in RL caused by substance P. Similarly, in 6 animals exposed to inhaled capsaicin, phosphoramidon significantly increased capsaicin responsiveness when compared to 6 capsaicin-exposed animals not treated with phosphoramidon. Phosphoramidon-induced augmentation of the airway responsiveness to substance P and to capsaicin was not simply the result of a nonspecific increase in airway smooth muscle responsiveness because phosphoramidon failed to potentiate the bronchoconstrictor response to inhaled acetylcholine. These results suggest the enkephalinase plays an important role in modulating in vivo bronchoconstrictor responses to substance P in guinea pigs. Therefore, alterations in enkephalinase activity could contribute to in vivo alterations in bronchoconstrictor responsiveness.     

Bronchial hyperresponsiveness to acetylcholine during acute pulmonary congestion in guinea pigs]

To understand the precise mechanism of bronchial hyperresponsiveness in patients with congestive heart failure, we studied the effect of mild pulmonary congestion on bronchial responsiveness to inhaled acetylcholine (ACh) in guinea pigs. We induced mild pulmonary congestion by inflation of a balloon placed in the left atrium, and maintained the left atrial pressure (Pla) at 10 mmHg for 30 minutes with continuous monitoring of lung resistance (RL) and dynamic compliance (Cdyn). Furthermore, we determined the provocative concentration of ACh producing 100% increase in RL (PC100-ACh), before and during balloon inflation. In animals with propranolol pretreatment, but not in animals without propranolol pretreatment, mild pulmonary congestion caused slight increase in RL (N.S.) and significant decrease in Cdyn (p less than 0.01) and PC 100-ACh (p less than 0.01). Cutting of bilateral vagal nerves partially inhibited the decrease of PC100-ACh, but pretreatment with either phenoxybenzamine, indomethacin, AA-861 or OKY-046 had not effect. These results suggest that blockade of beta-adrenergic receptors and the vagal reflex, but not of alpha-adrenergic receptors or arachidonates, contributes to bronchial hyperresponsiveness during acute pulmonary congestion.     

Variability of pulmonary responsiveness to aerosolized histamine in normal rabbits

Considerable between-subject variability in pulmonary responsiveness to histamine has been reported in normal human subjects, dogs, guinea pigs, and rhesus monkeys, but rabbits have not been studied. We determined the between- and within-rabbit variability of pulmonary histamine responsiveness in 34 anesthetized and mechanically ventilated New Zealand White rabbits. In 30 rabbits, 5 breaths of aerosolized histamine were delivered in 9 increasing concentrations ranging from 0.01 to 100 mg/ml. Eleven of 30 rabbits were rechallenged with histamine on 1-4 additional occasions over a 3-week period. In the remaining 4 rabbits, 9 doses of distilled H2O were aerosolized to determine the degree of spontaneous variability in measurements of lung resistance (RL) and dynamic lung compliance (Cdyn). We defined an increase in RL of greater than 50% of baseline (TD50RL) and a decrease in Cdyn of greater than 25% of baseline (TD25Cdyn) as being significant based on observations in these 4 rabbits. These limits exceeded the 99.9 percentile of spontaneous variability in RL and Cdyn. Pulmonary responsiveness to histamine varied widely, with a greater than 10,000-fold range in TD50RL and a 1,000-fold range in TD25Cdyn between the most and least sensitive rabbits. The variability of this responsiveness was log-normally distributed. It was not correlated with age, sex, or baseline RL and Cdyn. In contrast, within-rabbit responses to histamine challenge were quite reproducible. Five of 30 rabbits were killed at the conclusion of their histamine challenges for pathologic examination of their lungs. No evidence of airway inflammation was found.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of superoxide anions in airway hyperresponsiveness induced by cigarette smoke in conscious guinea pigs

To investigate the involvement of superoxide in airway hyperresponsiveness and bronchoconstriction induced by cigarette smoke (CS), we evaluated the effects of superoxide dismutase (SOD), a scavenger of superoxide anion, and apocynin, an inhibitor of superoxide anion-generating NADPH oxidase in phagocytes, on the airway responses induced by CS in conscious guinea pigs. Airway responsiveness was assessed by PC_2OOMch, the concentration required to produce a doubling in the baseline specific airway resistance (sRaw) to an inhaled methacholine aerosol, in nonanesthetized spontaneously breathing animals. Before being exposed to ten puffs of CS, animals inhaled either SOD (5,000 units/ml or 25,000 units/ml) or vehicle. Although SOD did not affect PC_2OOMch, in the air control group, this agent significantly reduced the CS-induced airway hyperresponsiveness. Repeated administration of apocynin (12 mg/kg for 4 days) did not affect PC_2OOMch, after exposure to CS. These data suggest that the superoxide from CS was involved in the airway hyperresponsiveness induced by CS, whereas phagocytic reactive oxygen species were not. The data also suggest a potential therapeutic role for antioxidants in airway hyperresponsiveness. Offprint requests to: Takao Okubo     

Increased airway responsiveness and decreased alveolar attachment points following in utero smoke exposure in the guinea pig

Maternal smoking during pregnancy has been shown to result in abnormalities in lung function in newborn infants, including reduced expiratory flow and increased airway responsiveness to inhaled agonists. The mechanisms by which this occurs remain unclear. Using a guinea pig model of in utero smoke exposure, we measured airway responsiveness and lung morphology in a group of neonatal guinea pigs 21 d after delivery. Pregnant guinea pigs were exposed to cigarette smoke from Day 28 to term (Day 68 of gestation). After delivery newborn animals did not receive any smoke exposure. Airway wall thickness, smooth muscle area, and the number of points where the alveoli attached to the airway adventitia were measured. Airway responsiveness was increased (p < 0.05) and the mean distance between alveolar attachment points was increased (mean 0.052 +/- SE 0.001 mm versus 0.046 +/- 0.001, p = 0.001) in animals exposed to cigarette smoke in utero compared with nonexposed animals. Although not statistically significant, both the inner and outer airway wall and the smooth muscle area were greater in exposed animals compared with nonexposed animals. The increased mean distance between alveolar attachments in the smoke-exposed group was the result of a reduction in the number of attachments and an increase in the outer airway wall perimeter. These findings suggest that the increased airway responsiveness observed in postnatal animals, subsequent to in utero cigarette smoke exposure, may be the result of decreased alveolar attachment points to the airways and changes in airway dimensions.     

The requirement for platelets in allergen-induced late asthmatic airway obstruction. Eosinophil infiltration and heightened airway responsiveness in allergic rabbits

In these studies, we have used an allergic rabbit model to investigate the role of platelets in the late asthmatic response (LAR) by depleting platelets with a guinea pig antirabbit platelet antiserum (APAS). Allergen exposure of immunized rabbits pretreated with normal guinea pig serum (NGPS) to serve as a control resulted in an early- and late-phase obstructive airway response that persisted for 6 h. When the immunized animals were pretreated with APAS, the magnitude of the LAR in terms of dynamic compliance was reduced by 86.2% (p less than 0.03), but there was no difference in the early response curve. Allergen challenge of animals treated with NGPS resulted in an increased bronchial responsiveness to inhaled histamine: PD50 Cdyn geometric mean +/- SEM before, 2.36 mg/ml (3.43-1.64); after, 0.60 mg/ml (0.67-0.54) (p less than 0.01). PD50 RL before, 1.78 mg/ml (2.4-1.32); after, 0.58 mg/ml (0.81-0.47) (p less than 0.05). In contrast, when animals were treated with APAS, there was a significant inhibition of allergen-induced airway hyperresponsiveness to inhaled histamine: PD50 Cdyn geometric mean +/- SEM before, 1.42 mg/ml (2.06-0.98); after, 1.10 mg/ml (1.41-0.86) (p less than 0.4). PD50 RL before, 1.62 mg/ml (2.22-1.39); after, 1.05 mg/ml (1.35-0.82) (p greater than 0.4). Analysis of bronchoalveolar lavage fluid revealed an increase in the number of neutrophils and eosinophils after allergen exposure in control animals (p less than 0.01). However, in animals rendered thrombocytopenic, the number of eosinophils, but not neutrophils, was significantly reduced (p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)     

脂多糖和甲双吡丙酮诱发形成豚鼠运动性哮喘模型

目的建立一种接近临床特点的运动性哮喘动物模型。方法豚鼠２７只分４组。实验组（Ａ组）用脂多糖（１ｍｇ／ｋｇ）和甲双吡丙酮（５０ｍｇ／ｋｇ）腹腔注射，４天后测定气道阻力和动态肺顺应性基础值，８小时后进行运动试验并复测上述指标。对照组有３组（Ｂ、Ｃ、Ｄ组）；分别为腹腔注射脂多糖和甲双吡丙酮不运动组、腹腔注射生理盐水运动组和腹腔注射生理盐水不运动组。结果实验组豚鼠在运动后肺阻力增高、动态肺顺应性降低，而３个对照组上述指标变化均无统计学意义。结论脂多糖和甲双吡丙酮腹腔注射可诱发形成豚鼠运动性哮喘模型     

Mechanism of airway narrowing caused by inhaled platelet-activating factor. Role of airway microvascular leakage

In order to study the mechanism of airway narrowing after inhaled platelet-activating factor (PAF) we measured concomitant changes in lung resistance (RL) and in airway microvascular leakage in anesthetized guinea pigs. RL and its recovery after hyperinflation at 5 min were measured until 6 min after PAF aerosol (0.1, 0.3, 1, and 3 mM), and in the case of 3 mM PAF also until 10 min. Microvascular leakage in trachea, main bronchi, and proximal and distal intrapulmonary airways was determined by measurement of extravasated Evans blue dye content. For comparison, the responses to inhaled histamine (3 mM) and 5-hydroxytryptamine (5HT) (3 mM), which act directly on airway smooth muscle, were also examined. Inhaled PAF increased RL dose-dependently, with a maximal response (peak RL) at 4 min after the inhalation, whereas the response to histamine or 5HT was maximal within a few seconds after the inhalation. Peak RL (cm H2O/ml/s) was significantly less after PAF (1.03 +/- 0.09) than after histamine (8.39 +/- 1.07) or 5HT (18.3 +/- 6.48), although there was no significant difference in RL after hyperinflation (recovery RL). No additional increase in RL was seen between 5 and 10 min after exposure. PAF caused a dose-dependent increase in Evans blue dye extravasation; 3 mM PAF induced significantly higher leakage than did histamine or 5HT at all airway levels at 6 min. PAF did not cause any additional extravasation of Evans blue dye at 10 min compared with that at 6 min after exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiopulmonary effects of a brief exposure to cigarette smoke in the guinea pig

To investigate whether the acute inflammatory response produced by acute cigarette smoke exposure is associated with alterations in pulmonary and cardiovascular function, using a respirator we exposed 8 guinea pigs to 350 ml of cigarette smoke diluted in 2,000 ml room air for 10 min. Lung volumes, pressure volume curves and flow volume curves were performed. Measurements of pulmonary artery pressure, systemic pressure, heart rate and cardiac output were taken at baseline, immediately after the smoke exposure, and 1.5 h after smoke exposure. Aliquots of peripheral blood for total white cell count and differential count were obtained. After animal sacrifice, the right lung was lavaged and white cell count and differential count performed. We found that acute exposure to cigarette smoke produced a peripheral blood neutrophilia which rose progressively from a baseline of 36.3 +/- 8% to a maximum of 72.2 +/- 7.7% at 1.5 h after exposure. There was pulmonary neutrophilia with 24.6 +/- 6.3% neutrophils in the lavage fluid of the smoke-exposed animals compared to 8.4 +/- 4.3% in the control animals. Immediately after smoke exposure, there was acute airflow obstruction with a decrease in the peak flow and forced expiratory flow between 25-75% vital capacity. This was associated with airtrapping, as shown by a transient increase in residual volume. There was a slight decrease in systemic blood pressure in the smoke-exposed animals associated with a nonsignificant decrease in the heart rate, and the cardiac output remained stable.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchoconstriction and delayed rapid shallow breathing induced by cigarette smoke inhalation in anesthetized rats

Bronchomotor and ventilatory responses to inhalation of cigarette smoke (50% concentration, 6 ml) were studied in anesthetized and vagotomized Sprague-Dawley rats. Low-nicotine cigarette smoke did not cause any detectable delayed response, whereas high-nicotine cigarette smoke induced rapid, shallow breathing, and a marked increase in airway resistance (RL). The increase in f reached a peak (delta f = 43 +/- 8%) at the 5th breath after the onset of smoke inhalation, preceding both the decrease in VT (delta VT = -27 +/- 4%) and the increase in RL (delta RL = 89 +/- 19%); the latter 2 reached their peaks at approximately the 10th breath, displaying a similar temporal pattern of responses between them. The bronchomotor response to high-nicotine cigarette smoke was slightly attenuated but not prevented by prior administration of isoproterenol (0.2 mg/kg, intravenously [iv]), nor was the smoke-induced rapid, shallow breathing. In contrast, prior administration of mecamylamine (0.9 mg/kg, iv) completely abolished both the bronchomotor and ventilatory responses to smoke inhalation, indicating that nicotine is the primary causative agent responsible for these changes.     

In vivo bronchodilator activity of nifedipine in the guinea pig

We administered histamine subcutaneously to anesthetized guinea pigs to induce prolonged bronchoconstriction and then tested the effect of intravenously administered nifedipine on pulmonary resistance (RL) and dynamic compliance (Cdyn). One mg of subcutaneously administered histamine caused RL to increase by an average of more than 250% and Cdyn to fall on average to 26% of baseline; mean RL remained more than twice baseline, and mean Cdyn remained less than half baseline for 80 min. Intravenously administered nifedipine 3 micrograms/kg and ethanol (diluent) administered 25 min after histamine had no effect on RL but caused a slightly greater fall in Cdyn than in the control animals treated with histamine alone. Nifedipine 30 micrograms/kg, however, exhibited significant bronchodilator activity: 35 min after nifedipine 30 micrograms/kg, RL decreased on average to 41 +/- 17% above baseline (p less than 0.02), and Cdyn increased to 49 +/- 5% below baseline (p less than 0.0001). By comparison, isoproterenol (0.3 to 3.0 micrograms/kg) caused bronchodilation of more rapid onset (within 1 min) and shorter duration of action (approximately 10 min). Thus, we were able to demonstrate bronchodilator activity of nifedipine in vivo, as had been predicted by in vitro studies of guinea pig and human tracheal strips. These results would appear to justify continued exploration of the potential role for calcium channel blockers in the treatment of obstructive lung disease.     

Capsaicin inhibits airway hyperresponsiveness but not lipoxygenase activity or eosinophilia after repeated aerosolized antigen in guinea pigs

To evaluate the role of tachykinins in airway hyperresponsiveness following repeated aerosolized antigen challenge in guinea pigs, we treated 12 guinea pigs with capsaicin (105.6 mg cumulative dose given subcutaneously over 5 days) after sensitization to ovalbumin (OA) and before three repeated OA aerosol challenges per wk for 4 to 5 wk. Ten guinea pigs received identical OA sensitization and challenges without capsaicin treatment, and four of eight nonsensitized controls received capsaicin followed by saline challenges. Capsaicin treatment did not alter antibody responses to OA as assessed by passive cutaneous anaphylaxis, nor did it alter lipoxygenase products from OA-stimulated bronchial tissue in vitro. Capsaicin completely inhibited the increased pulmonary resistance (RL) to acetylcholine produced by repeated aerosolized OA, whereas it did not alter baseline RL or acetylcholine responses of controls. Capsaicin did not alter airway eosinophilia induced by repeated aerosolized OA. We conclude that neuropeptides play an important role in antigen-induced airway hyperresponsiveness without altering antibody levels, lipoxygenase mediator production, or airway eosinophilia.     

Airway hyperresponsiveness and inflammation induced by toluene diisocyanate in guinea pigs

We examined the changes in airway responsiveness to increasing doses of an acetylcholine aerosol in anesthetized and ventilated guinea pigs 2, 6, or 24 h after exposure to 2 ppm toluene diisocyanate (TDI) or 2 h after exposure to air or 1 ppm TDI. Pulmonary resistance (RL) after the animals inhaled a buffered saline aerosol was used as baseline and was similar for air and TDI groups. The concentration of acetylcholine calculated to cause a 200% increase in RL was significantly lower for animals studied at 2 h (0.68%) or at 6 h (0.77%), but not at 24 h (2.39%), after TDI than for air animals (3.07%). The increase in airway responsiveness in the TDI-exposed animals was associated with histologic changes in the trachea and intrapulmonary airways. Exposure to 2 ppm TDI caused a patchy loss of cilia, shedding of epithelial cells into the airway lumen, and an influx of inflammatory cells into the trachea and other airways. In the lamina propria of the trachea, the concentration of extravascular polymorphonuclear leukocytes (PMN) was 13- to 26-fold greater in animals studied 2 or 6 h after exposure to 2 ppm TDI or at 2 h after 1 ppm TDI than in animals exposed to air. The concentration of PMN in the epithelium was significantly increased only in animals examined 2 h after 2 ppm TDI. Exposure to TDI also caused an influx of eosinophils into the tracheal mucosa. This influx occurred later and was more persistent than the influx of PMN. These results indicate that a single exposure to TDI can cause an increase in airway responsiveness that is associated with epithelial injury and acute airway inflammation.     

Reflex bradypnea elicited by cigarette smoke inhaled through an isolated larynx

The respiratory reflex responses elicited by laryngeal exposure to cigarette smoke were studied in 23 chloralose anesthetized dogs. A balloon-in-box system was connected to the breathing circuit, which allowed smoke to be inhaled spontaneously through an isolated larynx while preserving its normal respiratory flow and pressure. Our results in this study showed the following. (1) Two tidal breaths of cigarette smoke inhaled through the larynx triggered a mild but consistent bradypnea: expiratory duration (TE) increased from a control of 3.13 +/- 0.18 sec (mean +/- SEM) to a peak of 4.07 +/- 0.24 sec during smoke inhalation. The slowing of respiration occurred only during the period of smoke inhalation and returned quickly toward control after resuming air breathing. (2) No concomitant cardiovascular response was detected in these animals. (3) There was no significant difference in the prolongation of TE between responses to low- and high-nicotine cigarette smoke. (4) The bradypneic response to smoke was completely abolished by application of topical anesthetic (lidocaine hydrochloride) to the mucosa of this airway segment. These results suggest that the smoke-induced reflex bradypnea is probably elicited by a stimulation of laryngeal afferents.