Differential responses of tissue viscance and collateral resistance to histamine and leukotriene C4

Alterations in tissue viscance (Vti) and collateral resistance (Rcoll) are both used as indexes of peripheral lung responses. However, it is not known whether the two responses reflect the effects of activation of the same contractile elements. We measured differential responses in Vti and Rcoll to histamine and leukotriene (LT) C4 to determine whether each evoked a similar pattern of response. Using the wedged bronchoscope constant-flow technique, we measured Rcoll in lobar segments of anesthetized, paralyzed, open-chest, mechanically ventilated mongrel dogs. In addition, we measured (with an alveolar capsule) alveolar pressure (PA) within the segment under study. This allowed us to calculate Vti, the component of the PA change in phase with segment flow. Rcoll and Vti measurements were obtained under base-line conditions and after local delivery of aerosols generated from histamine and LTC4. In five out of five lobes studied with both histamine and LTC4, the fractional Rcoll response to histamine was greater than the fractional Rcoll response to LTC4. In contrast, in four out of five lobes examined, the fractional increase in Vti accompanying the histamine response was less than the fractional increase in Vti accompanying LTC4 administration. These data suggest that anatomically distinct contractile elements influence Vti and Rcoll insofar as LTC4 and histamine evoke quantitatively different changes in these two indexes of peripheral lung responses.     

Methacholine-induced airway reactivity of inbred rats

Dose-response curves to inhaled aerosolized methacholine chloride (MCh) were obtained in anesthetized spontaneously breathing rats. Thirty rats (10/strain), randomly selected from highly inbred ACI, Lewis (L), and Brown Norway (BN) strains and 40 rats (20/strain) from similarly inbred Wistar-Furth (WF) and Buffalo (Buf) strains were studied. Airway responses were quantitated from changes in pulmonary resistance (RL) and airway reactivity was calculated as the dose of MCh required to increase RL to 150% (ED150RL) and 200% (ED200RL) of base line. There were no statistically significant differences in ED150RL and ED200RL among the five rat strains. Large interindividual variability was present as evidenced by 128-fold differences in ED150RL and ED200RL between the least and most sensitive animal of the same strain. In contrast, seven animals studied repeatedly on different days had values of ED150RL that differed by an average of only 2.9-fold (range 1.6-5.3). Thirteen rats that were studied on two occasions separated by an interval of 3 mo showed no systematic changes in airway reactivity. We conclude that airway reactivity to inhaled methacholine in anesthetized nose-breathing rats is not strain related, and despite animals of a given strain being genetically identical, the variability in airway reactivity within strains suggests that environmental rather than genetic factors are the major determinants of that reactivity.     

Interstitial fibrosis and collateral ventilation

Interstitial fibrosis may increase resistance to collateral flow (Rcoll) because of decreased lung volume and destruction of collateral channels or it may decrease Rcoll because of emphysematous changes around fibrotic regions. In addition, if interstitial fibrosis involves a small region of lung periphery, interdependence from surrounding unaffected lung should produce relatively large changes in volume of the fibrotic region during lung inflation. We studied the effects of interstitial fibrosis on collateral airflow by measuring Rcoll at functional residual capacity (FRC) in nine mongrel dogs before and 28 days after the local instillation of bleomycin into selected lung segments. In six of these dogs Rcoll was also measured at a higher lung volume (transpulmonary pressure = 12 cmH2O above FRC pressure). Rcoll increased in fibrotic lung segments following local treatment with bleomycin. With lung inflation (high transpulmonary pressure) Rcoll fell a similar proportion in fibrotic and nonfibrotic lung regions. These observations suggest that collateral resistance increases in fibrotic segments because lung volume decreases or because collateral pathways are involved directly in the fibrotic process. Compensatory increases in collateral communications do not occur. In addition, pulmonary interdependence does not cause disproportionate increases in volume and decreases in Rcoll of the fibrotic region during lung inflation.     

Use of collateral airways to assess airway reactivity

We investigated the correlation between collateral airway reactivity and other indexes of lung reactivity in response to aerosol and intravenous (iv) challenges. In four anesthetized mongrel dogs, we measured the peripheral airway resistance (Rp) to gas flow out of a wedged lung segment in different lobes on multiple occasions. We obtained dose-response curves of peripheral airways challenged with iv histamine or aerosols through the bronchoscope. During the same iv bolus challenge, whole lung airway pressure (Paw) responses to histamine were also measured. On separate occasions, changes in lung resistance (RL) were measured after the whole lung was challenged with a histamine aerosol. Reactivity was assessed from the dose-response curves for Rp and RL as the PD50 (dose required to produce a 50% increase); for changes in Paw we calculated the PD15 (dose required to produce a 15% increase over baseline). Results for Rp showed considerably more variability among different lobes in a given animal with the aerosol challenge through the bronchoscope than with the iv challenge. With aerosol challenge there were no significant differences in the mean PD50 for Rp among any of the animals. However, with the iv challenge two of the dogs showed significant differences from the others in reactivity assessed with Rp (P less than 0.01). Moreover, the differences found in the peripheral airways with iv challenge reflected differences found in whole lung reactivity assessed with either iv challenge (Paw vs. Rp, r2 = 0.96) or whole lung aerosol challenge (RL vs. Rp, r2 = 0.84). We conclude that the measurement of the collateral resistance response to iv challenge may provide a sensitive method for assessing airway reactivity.     

Collateral flow resistance and time constants in dog and horse lungs

We studied collateral flow resistance in exsanguinated, excised lower lobes and accessory lobes of dog and horse lungs, respectively. A double lumen catheter obstructed a peripheral airway isolating a segment of the lobe. Oxygen flowed into the segment via a rotameter which measured flow (Vcoll) while the inner catheter recorded segment pressure (Ps). Gas delivered into the segment flowed out via collateral channels. Collateral flow resistance was calculated as (Ps - PL)/Vcoll, where PL = static transpulmonary pressure. Rcoll at PL = 20, 10, and 5 cm H2O averaged 0.24, 1.25, and 2.65 cmH2O.ml-1.s, respectively, in the dog, and 4.53, 6.00, and 12.62 cmH2O.ml-1.s in the horse. At a given PL, Rcoll measured during inflation. At constant PL, Rcoll increased with time at PL = 5 and 10 cmH2O, but was not time dependent at PL = 20 cmH2O. At constant PL, Rcoll increased at Vcoll increased. We conclude Rcoll is greater in horses than in dogs and is a function of PL, Ps - PL, and lung volume history in both species.     

Effects on body position and cholinergic blockade on mechanics of collateral ventilation

We studied the effects of position and cholinergic blockade on the mechanics of collateral ventilation in anesthetized paralyzed dogs. Resistance to collateral flow (Rcoll) is higher when an obstructed segment is dependent than when it is nondependent. Decreases of Rcoll in response to the local infusion of low oxygen mixtures are greater in dependent regions. We conclude that 1) changes in position affect Rcoll directly through local changes in lung volume related to the gradient of pleural pressure; 2) responses of collateral channels to local concentrations of CO2 and O2 are determined by ventilation perfusion relationships, which vary at different heights in the lung; and 3) resting cholinergic tone in the anesthetized dog varies at different heights in the lung.     

Vasoactive effects of substance P on isolated rabbit pulmonary artery

The vasoactive properties of substance P (SP) were studied in isolated rabbit pulmonary artery (PA) segments in vitro. In the absence of active base-line tone, noncumulative administration of SP (10(-11) to 10(-4) M) produced dose-dependent increases in PA tension. The peak isometric tension (Tmax) with SP was similar to the Tmax response to epinephrine; however, the doses of the agonist producing a threshold contraction and 25% of Tmax (ED25) were significantly lower for SP. In the presence of active base-line tone, induced by epinephrine or 5-hydroxytryptamine, SP produced transient PA relaxation which was directly related to the magnitude of the precontracted PA tension. Blockade of neurotransmission with tetrodotoxin (1 microgram/ml) and antagonists to alpha 1-adrenergic and histamine receptor binding had no effect on the contractile response to SP. On the other hand, PA contraction to an ED50 dose of SP was 1) inhibited by a mean of 33 +/- 10% (SE) following pretreatment with the cholinesterase inhibitor, neostigmine (10(-6) M) and 2) augmented by 52 +/- 21% with the cholinergic antagonist, atropine (10(-4) M). The latter also completely blocked the relaxation response to SP in precontracted PA. Similarly, removal of the PA endothelium also abolished the relaxation response to SP. In contrast, SP-induced contraction was markedly inhibited by the cyclooxygenase inhibitor, meclofenamate (1 microgram/ml), as well as the SP antagonist, D-Pro2, D-Trp7,9-SP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tracheal mucous transport in experimental canine asthma.

Tracheal mucous velocity (TMV) was measured in experimental canine asthma. All 10 sensitive dogs exposed to an aerosol of Ascaris suum extract showed a decrease in TMV to about one-third of base-line values within 45 min whereas only half of them (reactors) responded with bronchospasm as measured by a significant reduction in specific respiratory system conductance (SGrs). Mean TMV remained decreased at the end of the 2-h observation period when mean SGrs had returned to base-line values in the reactors. Neither TMV nor SGrs changed in nonsensitive animals who inhaled ragweed antigen. Aerosols of acetylcholine and histamine increased TMV thereby excluding these mediators as responsible for the impairment of mucous transport in asthma. Nebulization of A. suum antigen together with a selective antagonist of slow reacting substance of anaphylaxis (srs-a) produced a marked increase of TMV in all dogs regardless of whether or not bronchospasm was elicited. This suggests that the observed decrease in TMV may be related to the release of SRS-A during the immunologic reaction.     

Immunologic and nonimmunologic responsiveness in ragweed-sensitized dogs

The relationship between airway responsiveness to inhaled antigen and histamine, immunologic release of lung histamine, immunologic responsiveness of skin, and specific immunoglobulin E (IgE) antibodies were examined in 11 inbred allergic dogs immunized with extracts of ragweed and grass and 5 nonimmunized control dogs from the same colony. Airway responsiveness to antigen and histamine was characterized by the doses that increased the airflow resistance of the total respiratory system to twice the control values (ED200). Highly significant correlations were found between airway responsiveness and cutaneous responsiveness to antigen and other immunologic characteristics (e.g., IgE and histamine released from lung by inhaled antigen) in all dogs. In ragweed-sensitized dogs, there was an inverse correlation between immunologic responsiveness (reflected by the cutaneous response to antigen and histamine released from lung by inhaled antigen) and nonimmunologic responsiveness of airways (histamine ED200: r = 0.73, P less than 0.05 and r = 0.75, P less than 0.01, respectively). Antigen ED200 was also correlated with histamine release from lung after antigen inhalation (r = 0.74; P less than 0.01). We conclude that airway reactions to inhaled antigen in allergic dogs are dependent not only on immunologic factors but also on the degree of nonimmunologic airway responsiveness to histamine and that these factors are correlated inversely.     

Significance of thromboxane generation in ozone-induced airway hyperresponsiveness in dogs

To determine whether thromboxane A2 may be involved in ozone (O3)-induced airway hyperresponsiveness, we studied the effect of a thromboxane synthase inhibitor (OKY-046, 100 micrograms X kg-1 X min-1 iv) in five dogs exposed to O3. Airway responsiveness was assessed by determining the provocative concentration of acetylcholine aerosol that increased total pulmonary resistance by 5 cmH2O X l-1 X s. O3 (3 ppm) increased airway responsiveness as demonstrated by a decrease in acetylcholine provocative concentration from 2.42 (geometric SEM = 1.64) to 0.14 mg/ml (geometric SEM = 1.30). OKY-046 significantly inhibited this effect without altering pre-O3 responsiveness or the O3-induced increase in neutrophils and airway epithelial cells in bronchoalveolar lavage fluid. To further examine the role of thromboxane A2, we studied the effect of a thromboxane A2 mimetic, U-46619, on airway responsiveness in five additional dogs. U-46619 in subthreshold doses (i.e., insufficient to increase base-line pulmonary resistance) caused a fourfold increase in airway responsiveness to acetylcholine. Subthreshold doses of histamine had no effect. These results suggest that thromboxane A2 may be an important mediator of O3-induced airway hyperresponsiveness.     

Distribution of pulmonary responsiveness to aerosol histamine in dogs

Dose-response curves to aerosol histamine in 102 anesthetized, intubated, spontaneously breathing dogs revealed a spectrum of airway responsiveness with a greater than 40-fold difference between the most and the least sensitive animals. The frequency distribution of responses fits a log normal distribution. No correlation was found between sex, age, or control values of dynamic compliance (Cdyn) and lung resistance (RL) and the dose of histamine required to cause a response. Repetitive studies in 17 dogs observed for up to 20 mo showed that the dose at which an individual dog would respond was reproducible within a narrow range and that the differences between dogs were highly significant (P greater than 0.001). The long-term reproducibility of the response to aerosol histamine in individual dogs suggests that short-term reversible airway insults are not responsible for the range in responses noted between animals.     

Cholinergic neuromodulation by prostaglandin D2 in canine airway smooth muscle

To determine whether prostaglandin D2 (PGD2) modulates cholinergic neurotransmission in airway smooth muscle and, if so, what the mechanism of action is, we studied bronchial segments from dogs under isometric conditions in vitro. PGD2 (10(-8)-10(-5) M) elicited dose-dependent muscle contraction, which was reduced after blockade of muscarinic receptors, so that 50% effective dose (ED50) increased from 1.3 +/- 0.3 X 10(-6) to 3.9 +/- 1.0 X 10(-6) M by atropine (10(-6) M) (mean +/- SE, P less than 0.05). Physostigmine, at a concentration insufficient to alter base-line tension (10(-8) M), enhanced the PGD2-induced contraction and decreased ED50 to 6.4 +/- 0.5 X 10(-7) M (P less than 0.05). When added at the highest doses that did not cause spontaneous contraction (1.9 +/- 0.5 X 10(-7) M), PGD2 increased the contractile response to electrical field stimulation (1-50 Hz) by 21.9 +/- 6.6% (P less than 0.001). In contrast to this effect, the response to administered acetylcholine was not affected by PGD2. On the other hand, PGD2-induced augmentation of the response to electrical field stimulation (5 Hz) was further increased from 23.6 +/- 3.0 to 70.4 +/- 8.8% in the presence of physostigmine (10(-8) M) and was abolished by atropine but not affected by the alpha-adrenergic antagonist phentolamine or the histamine H1-blocker pyrilamine. These results suggest that the contraction of airway smooth muscle induced by PGD2 is in in part mediated by a cholinergic action and that PGD2 prejunctionally augments the parasympathetic contractile response, likely involving the accelerated release of acetylcholine at the neuromuscular junction.     

Enhanced airway responses to substance P after repeated challenge in guinea pigs

We performed three consecutive dose-response curves to rapid intravenous infusions of substance P (SP) in anesthetized, mechanically ventilated guinea pigs. The dose of SP required to decrease pulmonary conductance to 50% of its base-line value (ED50GL) decreased 2.8-fold (P less than 0.002) and 3.3-fold (P less than 0.001) on the second and third dose-response curves, respectively, compared with the first. SP did not alter airway responses to intravenous histamine but did cause a significant (3.7-fold) decrease in ED50GL for dose-response curves to intravenous capsaicin, an agent that causes bronchoconstriction by release of endogenous tachykinins. The neutral metalloendopeptidase inhibitor thiorphan (0.5 mg) and the angiotensin-converting enzyme inhibitor captopril (1.7 mg) both caused a marked enhancement of airway responses to SP observed on the first dose-response curve but did not alter the enhancement of SP-induced airway responses produced by repeated SP challenge. The anticholinergic atropine (5 mg/kg iv), the antihistamine mepyramine (8 mg/kg iv), and the cyclooxygenase inhibitor indomethacin (30 mg/kg ip) had no effect on the first SP dose-response curve. Atropine and mepyramine did not prevent the enhancement of SP responses observed with repeated challenge, but after pretreatment with either indomethacin or acetylsalicylic acid, dose-response curves to SP were reproducible. Our results indicate that airway responses to intravenous SP are enhanced with repeated SP challenge and suggest that cyclooxygenase products of arachidonic acid metabolism are involved in the mediation of this phenomenon.     

Collateral ventilation during high-frequency oscillation in dogs

Mechanics of collateral channels during high-frequency oscillatory ventilation (HFOV) were assessed in eight anesthetized dogs, using a modification of Hilpert's technique. Base-line functional residual capacity was measured with a body plethysmograph, with inspiratory efforts induced by phrenic nerve stimulation. The resistance (Rcoll) and time constant (Tcoll) of collateral channels at five lung volumes were measured during HFOV and positive end-expiratory pressure (PEEP). Rcoll and Tcoll were significantly higher during HFOV (P less than 0.001); the differences did not correlate with resting lung volumes. The calculated static compliance of the wedged segment was similar during HFOV and PEEP (P greater than 0.005). Mean pressures measured in small airways during HFOV corresponded to the midline between the inflation and deflation limbs of the static pressure-volume curves, indicating similar pressure-volume characteristics of the respiratory system during HFOV and static conditions. We conclude that HFOV increases resistance to gas flow through collateral channels but that this pathway may still be important in gas exchange.     

Hypocapnia does not alter collateral ventilation in sheep

Hypocapnic constriction has been proposed as a mechanism by which collateral pathways might rapidly alter ventilation to match perfusion. We studied the changes in response to hypocapnia with age in sheep, a species with collateral resistance (Rcoll) similar to those measured in humans. Measurements of Rcoll were made with either 5 or 10% CO2 and with air (hypocapnia) in 29 anesthetized sheep, ages 6 mo to 10 yr, with the wedged bronchoscope technique. Rcoll was 0.42 +/- 0.12, 0.58 +/- 0.18, 0.32 +/- 0.18, and 0.17 +/- 0.04 (SE) cmH2O.ml-1.min in 6-mo- and 1-, 2-, and 10-yr-old animals, respectively. These values were unchanged with hypocapnia. Despite the lack of a change in Rcoll with hypocapnia, administration of histamine aerosol (8 animals) through the bronchoscope increased Rcoll by 151 +/- 35% (P less than 0.05). These data suggest that although collateral pathways exist in sheep and are capable of constriction, they do not respond to hypocapnia. Furthermore, the response to hypocapnia is not influenced by age.     

Effect of age on lung mechanics and airway reactivity in lambs

We studied airway reactivity (AR) to aerosolized histamine, carbachol, and citric acid in lambs 1 mo of age to adulthood. Awake lambs were intubated and studied in a plethysmograph that measured dynamic compliance (Cdyn), resistance of the lung (RL), and functional residual capacity (FRC). Pleural pressure was measured using a Silastic balloon in the pleural space, and airway opening pressure (Pao) was measured using a catheter placed 1-2 cm distal to the nasotracheal tube. At the ages of 1, 3, 5, and 7 mo and adulthood, measurements of Cdyn, RL, and FRC were obtained in 46 sheep (22 males, 24 females). AR to carbachol, histamine, and citric acid was measured in each sheep in randomized order on three separate days by giving increasing concentrations of the drug in a noncumulative fashion. The dose that would have caused a 35% reduction in Cdyn (ED65Cdyn), a doubling of RL (ED200RL), or a 50% increase in FRC (ED150FRC) was calculated. In both males and females, base-line Cdyn increased (r = 0.81, P less than 0.01) with age, as did FRC (r = 0.87, P less than 0.01). There was no significant change in RL in either sex with age or in the group as a whole. There was a significant increase in AR to both histamine and carbachol with increasing age as measured by a decrease in ED65Cdyn (P less than 0.01 and P less than 0.05, respectively) with age. There was no significant change in AR with age as measured by RL or FRC for any of the three bronchoconstrictors tested.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological properties of canine intrapulmonary blood vessels

The contractile response of ring segments of large, medium, and small pulmonary arteries and veins of the dog to histamine, norepinephrine, and serotonin have been studied. The maximum contractile response to these drugs was normalized with respect to the maximal response obtained in stimulation with 127 mM K+. The small pulmonary artery was more reactive to histamine, norepinephrine, and serotonin when compared with large and medium pulmonary arteries. The medium and large pulmonary artery showed no difference in reactivity to histamine. However, the mean effective dose (ED50) values for these agonists among the different segments of pulmonary arteries showed no significant difference. The small and medium pulmonary veins demonstrated increased reactivity to histamine, but not norepinephrine and serotonin. The ED50 values also indicated that both small and medium veins were more sensitive to histamine when compared with the large pulmonary vein. The log concentration percent response curves for both small and medium pulmonary veins were displaced leftward (increased sensitivity) with respect to that for the large pulmonary vein. However, the reactivity and sensitivity to histamine between medium and small pulmonary veins were no different. The reactivity and sensitivity of different segments of pulmonary veins to norepinephrine and serotonin showed no significant differences among them. We conclude that histamine and other vasoactive substances, which are directly or indirectly related to mast cell degranulation, exert pharmacological effects on the pulmonary vasculature which possesses differential responsiveness at various levels of the vascular tree.     

Comparison of canine cardiovascular response to inhaled and intraperitoneally infused CO

We compared the hemodynamic and blood gas data from anesthetized dogs given 0.15% carbon monoxide (CO) to breathe (INH group) and from dogs injected with 100% CO intraperitoneally while breathing room air (ITP group). The animals were observed for a period of 150 min after reaching a level of 50% carboxyhemoglobin (HbCO). The time required to reach this level was similar for both groups, i.e., 102 +/- 54 and 90 +/- 21 min for the ITP and INH groups, respectively. The average HbCO% for the duration of the experiment was 58.3 +/- 2.4 and 62.9 +/- 1.5% for the ITP and INH groups, respectively. All the animals survived in each group. There was no significant difference in their hemodynamic response to CO, except for a higher mean systemic blood pressure in the INH group. This difference was also present during the base-line measurements, suggesting that it was not related to the effects of CO. Following the 150-min comparison period, we attempted to precipitate a terminal cardiovascular crisis by increasing the amount of CO given. The animals in the ITP group lived indefinitely as the result of a "plateau" effect in the level of HbCO%. The measured HbCO% level did not rise above 70% regardless of the amount of CO injected into the peritoneal space. Those in the inhalation group died with an average HbCO% of 80.0 +/- 3.5%. It is concluded that the toxic effect of CO is the result of impaired O2 delivery to the peripheral tissues.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tracheal narrowing during histamine-induced bronchoconstriction

To determine whether tracheal narrowing accompanies histamine-induced bronchoconstriction and whether a cholinergic reflex is involved in the tracheal and bronchial responses, we determined specific pulmonary resistance between the carina and the pleura (sRL) and tracheal volume (Vtr) with an indicator-dilution technique in conscious sheep. Immediately postdelivery of histamine aerosol (7.5 mg histamine base) mean sRL increased by 223% (P less than 0.05), and mean Vtr decreased by 25% (P less than 0.05). The duration of the changes was similar, with a return to base-line values within 60 min. With increasing doses of histamine up to 30 mg, there was a corresponding increase in mean sRL, whereas the maximum effect on Vtr was already reached after 7.5 mg of histamine. Atropine (0.2 mg/kg iv) increased mean Vtr by 77% (P less than 0.05) and blunted the histamine effects on sRL, whereas the histamine effects on Vtr were abolished. Intravenous histamine or carbachol aerosol had similar effects on sRL and Vtr. We conclude that in conscious sheep 1) histamine produces both tracheal and bronchial constriction with a similar time course, 2) there is a base-line vagal tone in the trachea and not the bronchi, 3) the cholinergic reflex component of histamine-induced constriction is greater in the trachea than the bronchi, and 4) this difference between the trachea and bronchi is not due to differential aerosol deposition or cholinergic responsiveness.     

Tachyphylaxis to inhaled aerosolized histamine in anesthetized dogs

Three consecutive dose-response curves to inhaled aerosolized histamine, separated by 1-h intervals, were obtained in 20 anesthetized mongrel dogs. In general, successive histamine dose-response curves shifted progressively rightward. Changes in pulmonary resistance (RL) and dynamic compliance (Cdyn) in response to low concentrations of histamine were reproducible, but responses to high concentrations (sufficient to at least double RL or decrease Cdyn by at least 30%) decreased on successive dose-response curves. The concentration of histamine required to double RL increased significantly (P less than 0.05) from 1.01 mg/ml on the first to 1.62 and 2.02 mg/ml on the second and third dose-response curves. In contrast, consecutive methacholine dose-response curves were not significantly different. Indomethacin pretreatment (5 mg/kg iv) prevented histamine tachyphylaxis, whereas atropine (4 mg iv) did not. However, indomethacin did not alter base-line pulmonary mechanics or histamine responsiveness as measured on the first dose-response curve. We conclude that tachyphylaxis to inhaled aerosolized histamine occurs in anesthetized dogs. Our results are consistent with an important role for endogenous prostaglandins in modulating the airway responses to repeated histamine exposures.