Acute Bronchoconstrictor Response Research Articles

Molecular-weight-dependent effects of nonanticoagulant heparins on allergic airway responses.

We have hypothesized that antiallergic activity of inhaled heparin is molecular weight dependent and mediated by "nonanticoagulant fractions" (NAF-heparin). Therefore, we studied comparative effects of high-, medium-, and ultralow-molecular-weight (HMW, MMW, and ULMW, respectively) NAF-heparins on acute bronchoconstrictor response (ABR) and airway hyperresponsiveness (AHR) in allergic sheep. Specific lung resistance was measured in 23 allergic sheep, before and immediately after challenge with Ascaris suum antigen, without and after pretreatment with inhaled NAF-heparins. Airway responsiveness was estimated before and 2 h postantigen as the cumulative provocating dose of carbachol in breath units, which increased specific lung resistance by 400%. NAF-heparins attenuated ABR and AHR in a molecular-weight-dependent fashion. HMW NAF-heparin (n = 8) was the least effective agent: it attenuated ABR [inhibitory dose causing 50% protection (ID50) = 4 mg/kg] but had no effect on AHR. MMW NAF-heparin (n = 8) showed intermediate efficacy (ABR ID50 = 0.8 mg/kg, AHR ID50 = 1.4 mg/kg), whereas ULMW NAF-heparin (n = 7) was the most effective agent (ABR ID50 = 0.4 mg/kg, AHR ID50 = 0.2 mg/kg). ULMW NAF-heparin was 3.5 times more potent in attenuating antigen-induced AHR when administered "after" antigen challenge and failed to inhibit the bronchoconstrictor response to carbachol and histamine. In 15 additional sheep, segmental antigen challenge caused a marked increase in histamine in bronchoalveolar lavage fluid that was not prevented by any of the inhaled NAF-heparins. These data indicate that antiallergic activity of inhaled heparin is independent of its anticoagulant action and resides in the <2,500 ULMW chains. The antiallergic activity of NAF-heparins is mediated by an unknown biological action and may have therapeutic potential.

Airway endothelin levels in asthma: influence of endobronchial hypertonic saline challenge.

The pathophysiology of exercise-induced asthma is not well understood. Hypertonicity of the airway lining fluid resulting from loss of water due to hyperventilation is considered to play a role, but the precise mechanism by which hypertonicity can induce bronchoconstriction is unknown. Peptides of the endothelin (ET) family have potent smooth muscle contractile properties, and have been linked to airway narrowing in stable asthma. We postulated that ET release may contribute to the acute bronchoconstrictor response induced by a hypertonic stimulus. Seven male asthmatic subjects underwent local endobronchial challenge with hypertonic (3.6%) saline and, as a control, isotonic (0.9%) saline aerosols in separate bronchopulmonary segments. Bronchoalveolar lavage (BAL) was performed at both sites during the phase of immediate bronchoconstriction. Concentrations of immunoreactive ET and of the mast cell products, histamine, tryptase and prostaglandin D2, in BAL fluid were measured. Concentrations of ET in BAL fluid from the hypertonic saline-challenged sites were significantly lower than those in BAL fluid from sites exposed to isotonic saline (0.19 [0.11-1.24] fmol/mL vs. 0.40 [0.20-2.36] fmol/mL, P<0.05). Concentrations of histamine, tryptase, and prostaglandin D2 did not differ significantly between the two sites. These findings do not support the hypothesis that ET release within the airway lumen is involved in the bronchoconstrictor response induced by hypertonic saline.

Inhibition of allergic airway responses by inhaled low-molecular-weight heparins: molecular-weight dependence.

Inhaled heparin prevents antigen-induced bronchoconstriction and inhibits anti-immunoglobulin E-mediated mast cell degranulation. We hypothesized that the antiallergic action of heparin may be molecular weight dependent. Therefore, we studied the effects of three different low-molecular-weight fractions of heparin [medium-, low-, and ultralow-molecular-weight heparin (MMWH, LMWH, ULMWH, respectively)] on the antigen-induced acute bronchoconstrictor response (ABR) and airway hyperresponsiveness (AHR) in allergic sheep. Specific lung resistance was measured in 22 sheep before and after airway challenge with Ascaris suum antigen, without and after pretreatment with inhaled fractionated heparins at doses of 0.31-5.0 mg/kg. Airway responsiveness was estimated before and 2 h postantigen as the cumulative provocating dose of carbachol in breath units that increased specific lung resistance by 400%. All fractionated heparins caused a dose-dependent inhibition of ABR and AHR. ULMWH was the most effective fraction, with the inhibitory dose causing 50% protection (ID50) against ABR of 0.5 mg/kg, whereas ID50 values of LMWH and MMWH were 1.25 and 1.8 mg/kg, respectively. ULMWH was also the most effective fraction in attenuating AHR; the ID50 values for ULMWH, LMWH, and MMWH were 0.5, 2.5, and 4.7 mg/kg, respectively. These data suggest that 1) fractionated low-molecular-weight heparins attenuate antigen-induced ABR and AHR; 2) there is an inverse relationship between the antiallergic activity of heparin fractions and molecular weight; and 3) ULMWH is the most effective fraction preventing allergic bronchoconstriction and airway hyperresponsiveness.

A rationale for the use of nedocromil sodium in the treatment of asthma

A rationale for the use of nedocromil sodium in the treatment of asthma

Allergen-induced late-phase airways obstruction in the pig: mediator release and eosinophil recruitment.

The aim of this study was to develop a novel model for studies of mediator mechanisms involved in the late asthmatic reaction in the lower airways, by using the sensitized pig. The release of histamine and cysteinyl-containing leukotrienes (cys-LTs), as well as the levels of inflammatory cells in blood and bronchoalveolar lavage fluid, were determined and their relationship to plasma cortisol levels and pulmonary airways obstruction was noted. Specific-pathogen free pigs were actively sensitized with Ascaris suum allergen, and one group of animals was treated with a cortisol-synthesis inhibitor (metyrapone) by constant intravenous infusion. Ascaris suum allergen was nebulized into the lower airways and total lung resistance, blood leucocyte count and urinary levels of methylhistamine and leukotriene E4 (LTE4) were followed for 8 h, whereafter bronchoalveolar lavage was performed for analysis of leucocytes. An increase in urinary methylhistamine and LTE4 was seen during the acute allergic reaction in both groups of pigs. Metyrapone treatment prolonged the acute release of histamine, and this was seen together with a prolonged acute bronchoconstrictor response. In metyrapone-treated pigs, a continuous release over 8 h was seen for cys-LTs, but not for histamine. A late blood eosinophilia was also seen in metyrapone-treated animals, starting 4-6 h after allergen challenge. Late cys-LT release and eosinophilia were absent in non-metyrapone-treated animals. These results suggest that allergen-induced late release of cys-LTs as well as blood eosinophilia occur simultaneously with late-phase airways obstruction in the pig, and that all these reactions are prevented by high levels of endogenous cortisol.

Allergen-induced late-phase airways obstruction in the pig: the role of endogenous cortisol

In developing a novel model for studies of the allergen-induced late-phase airways obstruction, by using the pig, the importance of endogenous cortisol levels was examined by the use of metyrapone, a cortisol-synthesis inhibitor. Specific-pathogen free pigs were actively sensitized with Ascaris suum allergen. One group of pigs was treated with a constant infusion of metyrapone in order to maintain low levels of plasma cortisol. Ascaris suum allergen was nebulized into the lower airways and plasma cortisol and catecholamine levels, total lung resistance and dynamic compliance, blood gases and pH, and blood flow in the bronchial circulation were continuously recorded for 8 h. At the time of allergen challenge, the plasma cortisol levels in sensitized pigs were 455 +/- 37 nM and 40.1 +/- 3.8 nM in non-metyrapone-treated and metyrapone-treated pigs, respectively. No difference was seen between the magnitude of the acute bronchoconstrictor response in the two groups. A late airways obstruction, starting at about 4 h, developed only in pigs with low cortisol levels, whereas a late increase in blood flow in the bronchial circulation was seen in both groups, even if a late airways obstruction was absent. Plasma adrenaline did not seem to influence the late-phase reaction. These results suggest that endogenous cortisol levels, but not adrenaline, modify the late response to allergen in the pig. Furthermore, it is suggested that the pig is a suitable model for studies of allergic reactions in the airways, if metyrapone is used to keep plasma cortisol levels within a normal range.

Inhibition of antigen-induced airway and cutaneous responses by heparin: a pharmacodynamic study.

We have previously shown that heparin attenuates the acute bronchoconstrictor response and immediate cutaneous reaction (ICR) to antigen in allergic sheep. In the present investigation, we studied the pharmacodynamics of the antiallergic action of heparin. Specific lung resistance (sRL) was measured in eight sheep, allergic to Ascaris suum antigen, before and 5 min after inhalation challenge with the antigen. On different experiment days, antigen challenge was repeated after pretreatment with 1) aerosol heparin (1,000 U/kg) administered < or = 20 min, 6 h, 12 h, and 24 h and 2) intravenous heparin (1,000 U/kg) administered < or = 20 min, 1 h, 6 h, and 12 h before antigen challenge. sRL increased by 374 +/- 116% (SE) above baseline with antigen alone. Both aerosol and intravenous heparin attenuated the antigen effects on sRL in a time-dependent fashion. Prolonging the lag time between pretreatment and antigen challenge decreased the inhibitory effect of aerosol heparin; delta sRL was 31 +/- 29, 99 +/- 38, 142 +/- 40, and 306 +/- 60% for < or = 20-min, 6-h, 12-h, and 24-h pretreatment protocols, respectively. In contrast, prolonging the lag time increased the inhibitory effect of intravenous heparin: delta sRL was 246 +/- 64, 66 +/- 26, and 76 +/- 32% for < or = 20 min, 1 h, and 6 h, respectively. In seven additional sheep pretreatment with intravenous heparin (1,000 U/kg) attenuated the ICR also in a time-dependent manner; the inhibitory effect of heparin on ICR to antigen was enhanced 60% by increasing the heparin pretreatment interval from 20 to 60 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunologic mast cell-mediated responses and histamine release are attenuated by heparin.

Heparin has been shown to act as a competitive inhibitor of inositol 1,4,5-triphosphate (InsP3) receptors in various cell types. Because InsP3 is one of the second messengers involved in stimulus-secretion coupling in mast cells, it is possible that heparin may inhibit mast cell-mediated reactions. Therefore, in allergic sheep, we tested this hypothesis in two mast cell-mediated reactions induced by immunologic and nonimmunologic stimuli: immediate cutaneous reaction (ICR) and acute bronchoconstrictor response (ABR). In 12 sheep allergic to Ascaris suum antigen, the surface area of the skin wheal was determined 20 min after intradermal injection (0.05 ml) of increasing concentrations of specific antigen, compound 48/80, and histamine, without and after pretreatment with heparin (100, 300, or 1,000 U/kg i.v.). Antigen, compound 48/80, and histamine produced concentration-dependent increases in ICR. Heparin "partially" inhibited the ICR to antigen and compound 48/80 in a dose-dependent manner without modifying the ICR to histamine. The heparin preservative benzyl alcohol was ineffective. In 11 additional sheep, specific lung resistance was measured before and after inhalation challenges with antigen, compound 48/80, and histamine without and with aerosol heparin pretreatment (1,000 U/kg). Heparin blocked the antigen- and compound 48/80-induced bronchoconstriction without modifying the airway effects of histamine. In isolated human uterine mast cells, heparin inhibited the anti-immunoglobulin E- but not the calcium ionophore- (A23187) induced histamine release. These data suggest that heparin inhibits the ICR and ABR induced by stimuli that produce immunologic and nonimmunologic mast cell degranulation without attenuating the effects of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Involvement of inflammatory mediators in the airway responses to trimellitic anhydride in sensitized guinea-pigs.

1. We examined the effect of various pharmacological agents on the acute bronchoconstrictor response and airway microvascular leakage in a model of guinea-pig sensitization to trimellitic anhydride (TMA) a cause of low molecular weight occupational asthma in man. 2. Guinea-pigs were given intradermal injections of 0.1 ml of 0.3% TMA in corn oil; 21-28 days later, anaesthetized guinea-pigs were challenged with TMA conjugated to guinea-pig albumin by tracheal instillation. Changes in lung resistance were measured and airway microvascular leakage was quantified by measuring the extravasation of Evans blue dye into the airway tissue. 3. Sensitized guinea-pig (n = 9 in each group) were pretreated with chlorpheniramine (2.5 mg kg-1, i.v.), WEB 2086 (10 micrograms kg-1, i.v.), BW 4AC (50 mg kg-1, i.p.), nedocromil sodium (2% aerosol for 60 s) or vehicle alone. 4. Pretreatment with chlorpheniramine inhibited both the acute bronchoconstrictor response and the increase in airway microvascular leakage. WEB 2086 and nedocromil sodium partially inhibited the bronchoconstrictor response but had no significant effect on airway microvascular leakage. BW 4AC caused a non-significant reduction of the bronchoconstrictor response and airway microvascular leakage. 5. These results indicate that both the bronchoconstrictor response and the airway microvascular response in this model of sensitization is mediated to a large extent by histamine. PAF but not 5-lipoxygenase products also partially mediates the bronchoconstrictor response but not the airway microvascular leakage. Nedocromil sodium partially inhibits the bronchoconstrictor response only.

Nedocromil sodium inhibits airway hyperresponsiveness and eosinophilic infiltration induced by repeated antigen challenge in guinea-pigs.

1. Repeated exposure to ovalbumin aerosol produced significant increases in epithelial eosinophils of airways of all sizes and produced increased pulmonary resistance (RL) to inhaled acetylcholine (ACh) in guinea-pigs. 2. Nedocromil sodium 10 mg ml-1, by nebulization prior to each ovalbumin (OA) challenge inhibited both the airway eosinophilia and hyperresponsiveness to ACh. 3. Nedocromil sodium pretreatment (10 mg ml-1 by nebulization) 10 min prior to OA completely inhibited the acute bronchoconstrictor response to OA. 4. Our findings suggest that nedocromil sodium inhibits airway hyperresponsiveness by inhibiting eosinophilic infiltration, or by simultaneously inhibiting mechanisms involved in both processes.

Participation of the cysteinyl leukotrienes in the acute bronchoconstrictor response to inhaled platelet activating factor in man.

To determine whether the effects of platelet activating factor on the airways may be due to the production of leukotrienes we studied the effects of pretreatment with the selective cysteinyl leukotriene antagonist SK&F 104353-Z2 on the airway and cellular responses to inhaled platelet activating factor. Eight healthy men were studied in a randomised, double blind placebo controlled cross-over study. A single dose of platelet activating factor that caused a fall of at least 35% in specific airways conductance (sGaw) was determined initially for each subject. Challenge with this dose of platelet activating factor was then carried out on two further occasions after pretreatment with a single nebulised dose of SK&F 104353-Z2 or placebo. The % reductions in specific airways conductance and of partial flow at 30% of vital capacity (PVmax30) were less after SK&F 104353-Z2 than after placebo (22 versus 34 for sGaw, 19 versus 31 for PVmax30). The mean (95% confidence limits (CL] differences in the maximum % fall from control values for SK&F 104353-Z2 and placebo were -12.6 (-23.8, -1.4) for sGaw and -12.5, (-20.8 -4.2) for PVmax30. The mean % fall in neutrophil count was similar after SK&F 104353-Z2 (46%) and after placebo (50%) (95% CL of difference 13.6, 6.6). Bronchial responsiveness to methacholine did not increase above baseline values in any subject when measured two weeks after challenge by platelet activating factor. This study suggests that leukotrienes play a part in the response to platelet activating factor in man.

Effects of Platelet-Activating Factor on Rat Airways

Effects of platelet-activating factor (PAF) on the rat airways were investigated. Male Wistar rats were anesthetized, and PAF was inhaled into the lungs through a tracheal cannula for 5 min using an ultrasonic nebulizer. The bronchomotor response was measured with a modified Konzett-Rössler method in rats immobilized with decamethonium bromide. The inhalation of PAF caused a marked bronchoconstriction, dose-dependently, in a concentration range of 0.0001 to 0.01%. The bronchoconstrictor potency of PAF was about ten times higher than that of ACh. On the other hand, histamine inhalation gave only a slight bronchoconstriction even at the high concentration of 0.1%. The bronchomotor response to PAF was accompanied by a marked, sustained decrease in systemic blood pressure, in a dose-dependent manner. Repeated inhalations of PAF (0.001%) at an interval of 60 min resulted in a pronounced tachyphylaxis in the bronchoconstrictor response, but not in the hypotensive response. Combined inhalations of PAF with ACh or histamine did not produce a potentiation by PAF of the bronchoconstrictor responses to ACh and histamine. These findings show that PAF is a strong bronchoconstrictor agent in rats and that there is no interaction between PAF and other mediators in the acute bronchoconstrictor response.

Respiratory health and dust levels in cottonseed mills.

Four cottonseed mills in the southern United States contained high levels of total and respirable dust. A survey of 172 workers showed low prevalences of byssinosis (2-3%) and chronic bronchitis (4%). Mean baseline (out of dust) lung function values were normal. Mean functional declines over the working shift were present on Monday and absent on Friday, indicating an acute bronchoconstrictor response. Despite limitations in translating measured dust levels into estimates of individual exposures, the overall dose-response relationship seems to differ from that found in the cotton textile industry.

Vagally-Mediated Reflex Bronchoconstriction in Allergic Asthma

Our results cannot be explained by the classic theory of asthma and we believe that this theory must be modified. Although some direct, local constriction of airway smooth muscle may occur, a major component of the acute bronchoconstrictor response to antigen inhalation appears to involve a vagally-mediated reflex, possibly arising from epithelial irritant receptors in the airways.