Bronchial responsiveness to nonantigenic bronchoconstrictors in awake sheep

The experiments were designed to further characterize pulmonary responsiveness to nonantigenic aerosol bronchoconstrictors in unanesthetized sheep. The distribution of aerosol histamine responsiveness was described among 55 sheep. Within day reproducibility of aerosol histamine (n = 18) and carbachol (n = 8) responsiveness was studied and aerosol histamine and carbachol responsiveness were compared (n = 9). The effects of cyclooxygenase inhibition with meclofenamate (n = 7) and ibuprofen (n = 8) on pulmonary responsiveness to aerosol histamine was studied as was the effect of ibuprofen (n = 6) on pulmonary responsiveness to aerosol carbachol. A log normal unimodal distribution of pulmonary responsiveness to aerosol histamine was described. Within day pulmonary responsiveness to aerosol histamine was highly reproducible while pulmonary responsiveness to aerosol carbachol decreased slightly, but not significantly, on the second challenge. Pulmonary responsiveness to aerosol histamine correlated with pulmonary responsiveness to aerosol carbachol (r = 0.85, P less than 0.05). Meclofenamate did not significantly attenuate pulmonary responsiveness to aerosol histamine. Ibuprofen attenuated pulmonary responsiveness to aerosol histamine (P less than 0.05) but not to aerosol carbachol. These experiments supply basic information related to pulmonary responsiveness to nonantigenic bronchoconstrictors in awake sheep.     

Effects of aerosol histamine and carbachol on central and peripheral airflow resistance in sheep

Sixteen anesthetized artificially ventilated open-chest sheep were prepared with retrograde catheters to allow for measurement of dynamic compliance of the lungs (Cdyn), total airflow resistance of the lungs (RL), and central (Rc) and peripheral (Rp) airflow resistance. Twelve sheep received aerosol histamine and 12 sheep received aerosol carbachol. Eight sheep received and responded to both aerosol histamine and aerosol carbachol. Three sheep received both aerosol histamine and aerosol carbachol but failed to respond to both agents. Under base-line conditions, for the 16 sheep, 69% of total RL was located in the peripheral component, Rp, and 31% in the central component, Rc. Aerosol histamine caused only peripheral small airway changes while aerosol carbachol predominantly effected the central large airways. When aerosol histamine responsiveness, defined using Cdyn or Rp, was compared to aerosol carbachol responsiveness using Rc, a correlation was demonstrable (r = 0.84, n = 8, P less than 0.05). It is possible in sheep to cause relatively pure peripheral small airway and relatively pure central large airway changes by using different bronchoconstrictor agents. Aerosol histamine and aerosol carbachol responsiveness correlated with each other in these artificially ventilated anesthetized sheep.     

Evaluation of the mechanism of decreased airway responsiveness in lambs

In this study we investigated three possible mechanisms for the decreased airway responsiveness (AR) found in young lambs. To evaluate aerosol delivery, 6 adult sheep (9 mo-3 yr old) and 12 lambs (4-8 wk old) were challenged with aerosol (aH) and intravenous histamine (ivH). Awake animals were intubated and studied in a plethysmograph, which measured dynamic compliance (Cdyn), resistance of the lung, and functional residual capacity. AR to histamine was measured by administration of increasing concentrations of histamine until a significant change in lung mechanics occurred or until the maximum dose of histamine was given. In all six adult sheep, the response to both aH and iVH was a decrease in Cdyn. In two lambs Cdyn was decreased with both aH and ivH, in five lambs with neither, in three lambs with aH only, and in two lambs with ivH only. To examine the role of beta-adrenergic activity in determining AR, six adult sheep and six lambs received ivH and on a separate day ivH with propranolol pretreatment (p + ivH). The median effective dose of histamine that caused a reduction in Cdyn to 65% of normal saline control (ED65Cdyn) for the adult sheep given ivH was 3.60 (range 0.23-4.85) and 0.70 (range 0.49-8.0) micrograms.kg-1.min-1 for p + ivH (P = NS). The median ED65Cdyn for the six lambs was 8.0 micrograms.kg-1.min-1 for both ivH alone and p + ivH. To evaluate the role of airway smooth muscle (SM), AR to aH was quantitated in six adult sheep and six lambs, and then an open-lung biopsy was performed.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

Airway reactivity in ponies with recurrent airway obstruction (heaves)

We measured lung function and airway reactivity to histamine administered by aerosol in two groups of ponies. Principal ponies had a history of heaves, a disease characterized by recurrent airway obstruction when ponies are housed in a barn and fed hay; control ponies had no history of airway obstruction. Ponies were paired (principal and control) and measurements were made when principal ponies were at pasture and in clinical remission (period A), following barn housing when principal ponies had acute airway obstruction (period B), and after a further 1 and 2 wk at pasture (periods C and D). At periods A, C, and D dynamic compliance (Cdyn), pulmonary resistance (RL), arterial O2 tension (PaO2), and CO2 tension (PaCO2) of principals and controls did not differ. Barn housing (period B) decreased Cdyn and PaO2 and increased RL in principals but not controls. The ED65Cdyn (the dose of histamine to reduce Cdyn to 65% of base line) did not differ in principals and controls at periods A, C, and D. At period B, ED65Cdyn decreased by 2.5-log doses of histamine in principals while ED65Cdyn was not affected in controls. There was no correlation between changes in airway reactivity and changes in RL and Cdyn. We conclude that ponies in clinical remission from heaves are not hyperreactive to histamine aerosol. This model of lung disease is similar to some forms of industrial asthma in which hyperreactivity occurs only during acute airway obstruction. The lack of correlation between ED65Cdyn and the degree of airway obstruction suggests that the hyperreactivity of principal ponies to histamine aerosol cannot be explained solely by alterations in baseline airway caliber.     

Effects of atropine in ponies with recurrent airway obstruction

The effects of atropine on lung function and airway reactivity in two groups of ponies were measured. Principal ponies had a history of recurrent airway obstruction when housed in a barn and fed hay; control ponies had no history of airway obstruction. Principal and control ponies were paired, and measurements were made when principal ponies were in clinical remission (period A) and during an acute attack of airway obstruction (period B). Atropine did not alter pulmonary resistance (RL), dynamic compliance (Cdyn), or airway responsiveness in either group of ponies at period A or in the controls at period B. In principal ponies at period B, atropine did not alter Cdyn or the concentration of aerosol histamine required to decrease Cdyn to 65% of base line (ED65Cdyn) but reduced RL and the change in RL induced by 0.1 mg/ml histamine (delta RL0.1). It is likely that the latter observation was due to geometric changes in the airways, because the change in RL and in delta RL0.1 were significantly correlated. The results of this study show little resting bronchomotor tone in normal ponies, but a major portion of the increase in RL in principals at period B is mediated via muscarinic receptors. Little evidence exists for muscarinic receptor involvement in the response to aerosol histamine in either principal or control ponies.     

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.     

Role of circulating platelets and granulocytes in PAF-induced pulmonary dysfunction in awake sheep

The effects of a single intravascular bolus injection of platelet-activating factor (PAF) on pulmonary hemodynamics, lung mechanics, and lung fluid and solute exchange were studied in 13 chronically instrumented unanesthetized sheep. Since PAF has profound effects on both platelets and granulocytes, we investigated the effects of platelet and granulocyte depletion on the sheep's response to exogenous PAF. Sheep received PAF when granulocyte and platelets counts were normal and after platelet depletion with rabbit antisheep platelet antibodies (n = 5) or granulocyte depletion with hydroxyurea (n = 5). Sheep served as their own controls, and the order of experimentation was varied. Bolus injections of PAF had reproducible effects on pulmonary hemodynamics (pulmonary arterial pressure increased acutely to 85 +/- 3.7 cmH2O) and lung mechanics (dynamic compliance of the lungs decreased to 24.5 +/- 3.8% of base line and resistance to airflow across the lungs increased greater than 10-fold) and caused marked increases in lung lymph concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha. The single bolus injection of PAF also caused marked prolonged elevations in lung lymph flow and increases in the lymph-to-plasma protein concentration ratio for 3 h after PAF. PAF had profound effects despite platelet and granulocyte depletion. Platelet depletion slightly attenuated the pulmonary hypertension observed after PAF injection. Platelet depletion also attenuated the increases in thromboxane B2 concentrations in lung lymph, and lung mechanics normalized more rapidly in platelet-depleted sheep. There were no statistically significant effects of granulocyte depletion to less than 200 granulocytes/mm3 on any of the measured variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

Large-volume ventilation results in bronchoconstriction of Basenji-Greyhound dogs

We compared the effects of large-volume ventilation on airway responses to aerosolized histamine in anesthetized mongrel dogs with its effects in Basenji-Greyhound crossbred (B-G) dogs. Before bronchoconstriction, large inflations resulted in only small changes of dynamic compliance (Cdyn) and pulmonary resistance (RL) in both groups of dogs. After the induction of a moderate degree of bronchoconstriction with aerosolized histamine, large inflations had a more substantial effect; Cdyn increased by 7.5 +/- 2.3% (mean +/- SE; P less than 0.05), and RL decreased by 32 +/- 3.4% (P less than 0.001) in the mongrel dogs. In the B-G group, Cdyn increased by only 0.2 +/- 1.8% (NS), and RL increased by 29.3 +/- 9.2% (P less than 0.05); these changes differed significantly (P less than 0.05) from those observed in the mongrel dogs. Large-volume ventilation following the administration of indomethacin (10 mg/kg iv) and histamine increased Cdyn by 11.4 +/- 1.8% (NS vs. without indomethacin) and decreased RL by 43.9 +/- 3.4% (P less than 0.05) in the mongrel group. In the B-G group large-volume ventilation increased Cdyn by 7.6 +/- 1.7% (P less than 0.01) and decreased RL by 15.7 +/- 8.1% (P less than 0.05). Thus indomethacin enhanced the bronchodilator effects of large-volume ventilation in mongrel dogs and reversed the bronchoconstrictor effect of this maneuver on RL in B-G dogs.     

Lung mechanics and airway reactivity in sheep during development of oxygen toxicity

The causes of respiratory distress in O2 toxicity are not well understood. The purpose of this study was to better define the airway abnormalities caused by breathing 100% O2. Sheep were instrumented for measurements of dynamic compliance (Cdyn), functional residual capacity by body plethysmography (FRC), hemodynamics, and lung lymph flow. Each day Cdyn and FRC were measured before, during, and after the application of 45 min continuous positive airway pressure (CPAP) at 15 cmH2O. The amount of aerosol histamine necessary to reduce Cdyn 35% from baseline (ED35) was measured each day as was the response to aerosol metaproterenol. Cdyn decreased progressively from 0.083 +/- 0.005 (SE) 1/cmH2O at baseline to 0.032 +/- 0.004 l/cm H2O at 96 h of O2. Surprisingly, FRC did not decrease (1,397 +/- 153 ml at baseline vs. 1,523 +/- 139 ml at 96 h). The ED35 to histamine did not vary among days or from air controls. Metaproterenol produced a variable inconsistent increase in Cdyn. We also measured changes in Cdyn during changes in respiratory rate and static pressure-volume relationships in five other sheep. We found a small but significant frequency dependence of compliance and an increase in lung stiffness with O2 toxicity. We conclude that in adult sheep O2 toxicity reduces Cdyn but does not increase airway reactivity. The large reduction in Cdyn in O2 toxicity results from processes other than increased airway reactivity or reduced lung volume, and Cdyn decreases before the development of lung edema.     

Reduced sensitivity to beta-adrenergic agonists in Basenji-Greyhound dogs

To investigate the inhibitory effects of beta-adrenergic agonists and aminophylline on pulmonary responsiveness, we evaluated the ability of albuterol and aminophylline to attenuate pulmonary responses to aerosol challenge with methacholine and histamine in intact Basenji-Greyhound (BG) and selected mongrel dogs. Pulmonary responses were measured in untreated dogs and in dogs pretreated with albuterol (1 and 2.5 micrograms/kg) or aminophylline. Before aerosol challenge, baseline pulmonary resistance (RL) and dynamic compliance (Cdyn) were not significantly different between the BGs and the mongrels. In the untreated dogs, pulmonary responses to methacholine and histamine aerosols were not different between the BGs and the mongrels. Pretreatment with albuterol (1 microgram/kg) or aminophylline significantly attenuated the pulmonary response to methacholine in the mongrels but was without effect in the BGs. Albuterol (2.5 micrograms/kg) significantly attenuated the pulmonary response to methacholine in the BGs and the mongrels; however, this attenuation was significantly greater (P less than 0.05) in the mongrels than in the BGs. In response to histamine challenge, no differences were seen between the BGs and the mongrels in the control state (no pretreatment) or after pretreatment with albuterol or aminophylline. This study demonstrates that in BGs pulmonary responsiveness to methacholine but not histamine is resistant to inhibition by beta-adrenergic agonists. This may result from a qualitative or quantitative defect in either the cholinergic or beta-adrenergic receptor or to an abnormality distal to the receptors in the signal transduction mechanism at a site where the two signals interact.     

Noninvasive detection of airway constriction in awake guinea pigs

Tidal volume measured by the barometric method is very sensitive to increases in compression and expansion of alveolar gas, such as would be expected to occur during airway narrowing or closure. By comparing a barometric method tidal volume signal (VT') with a reference tidal volume (VT) obtained with a head-out pressure plethysmograph, a simple index related to gas compressibility effects was calculated (VT/VT'). Changes in this index were compared with decreases in dynamic compliance (Cdyn) during histamine aerosol challenge of 15 Charles River Hartley guinea pigs. Decreases in VT/VT' occurred during all aerosol challenges and were correlated with decreases in Cdyn (r = 0.84, P less than 0.001). Decreases in VT/VT' were most marked at Cdyn values of less than 50% of base line. At Cdyn of less than 15% of base line, VT' was 3.1-4.8 times the VT reference signal. No increase in total pulmonary resistance was noted, and Cdyn and VT/VT' returned to base line after histamine exposure was stopped. We conclude that gas compressibility effects become substantial during histamine-induced airway constriction in the guinea pig and that the VT/VT' ratio appears to provide a simple noninvasive method of detecting these changes.     

Pharmacology of aerosol leukotriene C4- and D4-induced alteration of pulmonary mechanics in anesthetized cynomolgus monkeys

Aerosol administration of solutions of 900 micrograms/ml of leukotriene C4 (LT) or D4 to cynomolgus monkeys produced dose-dependent, equipotent increases in pulmonary resistance (Rp) and decreases in dynamic lung compliance (Cdyn). Time to peak response was, in part, related to dose and ranged from 4 to 20 min. Both LTC4 and LTD4 were less potent than histamine. Aerosol pretreatment with the cyclooxygenase inhibitor indomethacin had no significant effect on either LTC4 or LTD4 dose-response curves; however, at the highest doses of these agonists a notable, nonsignificant inhibition of effects on both Rp and Cdyn was seen. Intravenous dl-propranolol had no effect on responses to LTD4. Aerosol pretreatment with FPL 55712 significantly (P less than 0.05) inhibited airway responses to both LTC4 and D4. In contrast, an intravenous infusion of FPL 55712 failed to block the bronchospastic activity of LTD4. In conclusion, cynomolgus monkeys are responsive to aerosol administration of LTC4 and LTD4, and the pharmacology of their responses appears to resemble that of man.     

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.     

Beta-adrenergic blockade in ponies with recurrent obstructive pulmonary disease

Ponies with recurrent airway obstruction have hyperresponsive airways during acute disease exacerbations but not during clinical remission. We examined the effect of beta-adrenergic blockade with propranolol on airway responsiveness to aerosol histamine in six ponies with recurrent airway obstruction and six age- and gender-matched controls. Measurements were made with principal ponies in clinical remission (period A) and during an acute period of airway obstruction (period B). beta-Adrenergic blockade did not change airway responsiveness, dynamic compliance (Cdyn), or pulmonary resistance (RL) in either group of ponies at period A or in the control ponies at period B. In principal ponies at period B, propranolol significantly increased RL but was without effect on Cdyn or airway responsiveness. We conclude that the beta-adrenergic system is involved in the control of central airway caliber in principal ponies at period B but that this system does not seem to be involved in the mechanism of airway hyperresponsiveness to histamine.     

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.     

Airway responses to inhaled ouabain and histamine in conscious guinea pigs

Tracheal Na+-K+-ATPase activity is positively correlated with in vivo airway responsiveness to histamine. We wondered whether this were a chance association or whether it was directly related to the mechanism of hyperreactivity. Therefore, we obtained dose-response curves to aerosols of histamine and ouabain in guinea pigs to determine whether an in vivo relationship existed between the excitatory effects of histamine and the enzyme-inhibiting effect of ouabain. Airway responsiveness to ouabain was measured as the ouabain concentration producing a 30% decrease in specific airway conductance (ED30) or that producing a half-maximal response (ED50). Responsiveness to histamine was measured either as ED30 or as ED50. Significant positive correlations were noted between the log ED50 of ouabain and log histamine ED30 or ED50 (r = 0.81 and 0.83, respectively; P less than 0.001), and between log ouabain ED30 and log histamine ED30 and ED50 (r = 0.76 and 0.77, respectively; P less than 0.002). Pretreatment with ouabain increased airway responsiveness to histamine (P less than 0.05). We suggest that in hyperreactive airways Na+-K+-ATPase serves a homeostatic function of preventing Na+ and Ca2+ loading of the cell and that it is not directly responsible for the hyperreactivity.     

Selective lung leukosequestration after complement activation

This study tests whether activated complement leads to a selective entrapment of polymorphonuclear leukocytes (PMN's) in the lungs. Awake sheep were infused for 5 min with zymosan-activated plasma (ZAP, 2.5 mg/ml) at a rate of 5 ml/min into the superior vena cava (IV, n = 4) or intra-arterially into the aortic arch or femoral artery (IA, n = 8). At the end of IV infusion, leukocyte counts fell from 8,862 to 1,631/mm3 (P less than 0.01). PMN counts across the lungs decreased by 74%. There were increases in plasma thromboxane (Tx) B2 from 114 to 2,733 pg/ml (P less than 0.01), mean pulmonary arterial pressure from 12 to 42 mmHg (P less than 0.01), and physiological shunt from 13 to 25% (P less than 0.05). Within 1 h lymph TxB2 levels had risen from 301 to 4,916 pg/ml (P less than 0.01), lung lymph flow (QL) rose from 3.7 to 11.1 ml/30 min (P less than 0.05), lymph-to-plasma protein ratio (L/P) remained unchanged at 0.63, and lymph protein clearance increased from 2.3 to 7.5 ml/30 min (P less than 0.05). Leukosequestration, quantitated by capillary PMN counting and by assaying the granulocyte marker myeloperoxidase, occurred relative to sham animals (P less than 0.05) in the lung and spleen but not in other organs. Intra-arterial ZAP infusion led to changes that were similar in magnitude and timing to the IV group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Central role of cyclooxygenase in the response of canine peripheral airways to antigen

We studied the effects of antigen aerosol challenge on the airways of the canine peripheral lung and examined the roles of cyclooxygenase products, histamine, and cholinergic activity in the responses. One-minute deliveries of 1:10,000 or 1:100,000 concentrations of Ascaris suum antigen aerosol through a wedged bronchoscope resulted in mean maximal increases in collateral system resistance (Rcs) of 415 and 177%, respectively, after 4-8 min. Repeated antigen challenge (1:100,000) resulted in significantly decreased responsiveness to antigen after the initial exposure (P less than 0.005). Bronchoalveolar lavage fluid obtained from the isolated, challenged segment had a significant increase in mean (+/- SE) prostaglandin D2 (PGD2) concentration vs. control (222.0 +/- 65.3 vs. 72.7 +/- 19.5 pg/ml; P less than 0.05); histamine concentrations were variable and not significantly different (4.1 +/- 2.6 vs. 1.2 +/- 0.2 ng/ml; P greater than 0.05). In nine experiments, cyclooxygenase inhibition significantly attenuated the antigen-induced increase in Rcs by 53.4% (P less than 0.001), and the concentration of PGD2 in lavage fluid was reduced by 96.0% (P less than 0.01). Blockade of histamine H1-receptors (n = 8) or cholinergic receptors (n = 7) did not significantly affect the airway response (P greater than 0.05). These data indicate that the canine peripheral lung responds in a dose-dependent manner to antigen aerosol challenge and exhibits characteristics of antigen tachyphylaxis. Results also suggest that cyclooxygenase products play a central role in the acute bronchoconstrictive response of the lung periphery.     

The Basenji-Greyhound dog model of asthma: leukocyte histamine release, serum IgE, and airway response to inhaled antigen

To understand the immunologic mechanisms underlying the variation in airway response to inhaled Ascaris antigen (AA) in Basenji-Greyhound (BG) dogs having hyperreactive airways, we examined the relationship between leukocyte histamine release, Ascaris-specific serum IgE, changes in pulmonary resistance (RL), and decreases in dynamic compliance (Cdyn). All Ascaris-sensitive BG dogs showing airway responses to AA aerosol challenge exhibited an antigen dose-dependent release of leukocyte histamine, with total leukocyte histamine ranging from 68 to 123 ng/10(7) cells. Airway response to inhaled antigen more closely correlated with antigen dose releasing 50% total leukocyte histamine (RL, r = 0.94); Cdyn, r = 0.82), than with circulating levels of antigen-specific IgE (RL, r = 0.68; Cdyn, r = 0.69). We conclude that the airway response of sensitized BG dogs to AA inhalations is more dependent on factors affecting mediator release from pulmonary sources than circulating specific reaginic antibody.