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PubMed1996

Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

BACKGROUND: Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied. MATERIALS AND METHODS: Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS. RESULTS: LPS induced the release of TX and caused increased airway resistance after about 30 min. Both TX formation and LPS-induced bronchoconstriction were prevented by treatment with the unspecific COX inhibitor acetyl salicylic acid, the specific COX-2 inhibitor CGP-28238, dexamethasone, actinomycin D, or cycloheximide. LPS-induced bronchoconstriction was also inhibited by the TX receptor antagonist BM-13177. The TX-mimetic compound, U-46619, increased airway resistance predominantly by constricting terminal bronchioles. COX-2-specific mRNA in lung tissue was elevated after LPS exposure, and this increase was attenuated by addition of dexamethasone or of actinomycin D. In contrast to LPS, platelet-activating factor (PAF) induced immediate TX release and bronchoconstriction that was prevented by acetyl salicylic acid, but not by CGP-28238. CONCLUSIONS: LPS elicits the following biochemical and functional changes in rat lungs: (i) induction of COX-2; (ii) formation of prostaglandins and TX; (iii) activation of the TX receptor on airway smooth muscle cells; (iv) constriction of terminal bronchioles; and (v) increased airway resistance. In contrast to LPS, the PAF-induced TX release is likely to depend on COX-1.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1996

The multilevel mechanical behaviour of the lung during induced bronchoconstriction.

The standard way of simulating obstructive lung disease in animals is by induced bronchoconstriction, where a bronchoactive agent is applied to the lungs either by inhaled aerosol or i.v. injection. This paper reviews some of the recent advances in our understanding of how lung mechanics in animals are affected by bronchoconstriction at both the microscopic and macroscopic levels. At the microscopic level, the alveolar capsule oscillator technique provides mechanical information at the level of a single acinus, and has shown that bronchoconstriction causes both spatial and temporal inhomogeneities throughout the lung. These inhomogeneities become more profound as lung volume is reduced, presumably because of reduced mechanical interdependence between adjacent lung regions. At the macroscopic level, studies of the time-evolution of lung impedance following a sudden application of bronchial agonist have provided evidence that regional mechanical inhomogeneities are the major contributor to impedance changes. Thus, an important general problem is to find out how the distributed regional (microscopic) mechanical properties of the lung determine its macroscopic properties. Computer models of the lung, such as those based on branching airway trees terminating in complex tissue impedances, are beginning to make this link.

Animals↗

PubMed1996

Beta 2- but not beta 1-adrenoceptors mediate the adrenergic component of reflex tracheal dilatation during bronchoconstriction in guinea pigs in vivo.

Involvement of beta 1- and/or beta 2-adrenoceptors in vagal reflex-mediated tracheal dilatation during bronchoconstriction was investigated using the in vivo guinea pig tracheo-bronchi separated preparation. Inhalation of 0.01% (w/v) histamine to the bronchial site produced vagal reflex-mediated tracheal constriction followed by dilatation slightly after bronchial constriction. The latter reflex dilatation was significantly inhibited not only by 1% propranolol, a nonselective beta-adrenoceptor antagonist, but also by 0.1% butoxamine and 0.01% ICI-118,551, selective beta 2-adrenoceptor antagonists. However, 0.1% atenolol, a selective beta 1-adrenoceptor antagonist failed to inhibit the dilatation. Furthermore, the dilatation was also inhibited by 0.1% guanethidine treatment or adrenalectomy. All of noradrenaline, adrenaline and cyclic AMP contents in the tissue of the tracheal site significantly increased during the reflex tracheal dilatation after bronchoconstriction. The increase in cyclic AMP was reduced by 1% propranolol. Furthermore, local treatment of the tracheal site with 0.01% noradrenaline or 0.01% adrenaline induced tracheal dilatation, which was significantly inhibited by 0.1% butoxamine or 0.001% ICI-118,551 but not by 0.1% atenolol. These results suggest that the reflex tracheal dilatation during bronchoconstriction may be mediated by mainly beta 2-adrenoceptors activated by adrenaline released from the adrenal medulla and by noradrenaline released from the adrenergic nerve terminals.

Administration, Inhalation↗

PubMed1997

Effect of surfactant inhalation on allergic bronchoconstriction in guinea pigs.

BACKGROUND: In the small airway, surfactant reduces surface tension, prevents liquid filling of bronchioles, thereby maintaining patency in the small airways. Recent reports demonstrated that surfactant dysfunction develops in experimental asthma in immunized guinea pigs. However, there are few reports concerning surfactant and lung function in an experimental asthma model. OBJECTIVE: To examine whether inhaled surfactant improves lung mechanics in antigen-induced bronchoconstriction in guinea pigs. METHOD: We developed a passively immunized guinea pig model for allergic bronchoconstriction induced by antigen inhalation. Using this model, we investigated the effect of inhaled exogenous surfactant, surfactant TA, on the airway opening pressure (Pao) after antigen challenge. RESULTS: Aerosol antigen challenge produced a gradual and long-lasting increase in Pao. Twenty minutes after antigen challenge, aerosolized surfactant TA, 20 mg/ml, was inhaled for 90 s, and it significantly reduced the Pao by 32.8% in 12 min, while a 10.2% reduction was observed in a control group in the same period. When surfactant TA was administered by 90-s inhalation before antigen challenge, it inhibited the Pao increase in a dose-dependent manner: mean inhibitory rates of Pao were 33.6% in surfactant TA 10 mg/ml and 61.9% in surfactant TA 20 mg/ml, respectively. CONCLUSION: Inhaled surfactant showed preventive and recovery effects on antigeninduced bronchoconstriction in an immunized guinea pig model.

Administration, Inhalation↗

PubMed1997

Differential distribution of elastic system fibers in control and bronchoconstricted intraparenchymatous airways in the guinea-pig lung.

The elastic system fibers were studied at the light microscopic level by using Weigert's resorcin-fuchsin method after oxidation. This study was designed to describe the distribution of these fibers in intrapulmonary guinea-pig airways and to characterize their conformational changes during bronchoconstriction induced by methacholine aerosol. Airways present a palisade of elastic system fibers just beneath the epithelial basement membrane; these fibers are also present in the adventitial connective tissue. Thin fibers link the fibers located in the palisade among themselves and also connect them to those fibers located in the bronchial adventitial tissue, by traversing the airway smooth muscle. During bronchoconstriction, the fibers located beneath the epithelial basement membrane are divided into two components: one follows the epithelial invaginations towards airway lumen, while the other population remains attached through airway smooth muscle to the fibers located in the adventitial connective tissue. At the ultrastructural level, the findings corroborated those of the light microscopy and in addition, disclosed that typical mature elastic fibers and also elaunin fibers attach directly to the basal lamina, a feature that has not been reported previously in other tissues studied. This configuration is compatible with the idea that fibers of the elastic system restrict the mucosal folding during bronchoconstriction, and may also provide energy to restore airway configuration to its normal status after contraction.

Animals↗

PubMed1998

Effects of inhaled KAA-276, a selective histamine H1 receptor antagonist, on antigen- and histamine-induced bronchoconstriction in animals.

The antiasthmatic profile of KAA-276 (1-[1-(4-fluorophenylmethyl)-1H-benzimidazole-2-yl]-5-[2-[4-(2- carboxethyl) phenyl]ethyl]-1,5-diazacyclooctane sulfate, CAS 167264-26-8), a newly synthesized histamine H1 receptor antagonist, given by inhalation as an aerosol was investigated and compared with the profiles obtained using other routes of administration. When given by inhalation, or by intravenous or oral routes, KAA-276 inhibited antigen-induced bronchoconstriction in rats with ID50 (a dose to inhibit the antigen-induced response by 50%) values of 0.054%, 1 mg/kg, and 51.2 mg/kg, respectively. KAA-276 prevented the histamine-induced wheal reaction in rats dose-dependently with ID50 values of 0.22% by inhalation, 0.18 mg/kg by the intravenous route, and 2.3 mg/kg by the oral route. To judge from these results, inhaled KAA-276, unlike intravenous or oral KAA-276, had no inhibitory effect on the histamine-induced wheal reaction at a dose (0.054%) that is effective against the antigen-induced airway asthmatic response. Inhaled KAA-276 suppressed antigen-induced bronchoconstriction in actively sensitized guinea pigs, and histamine-induced bronchoconstriction in monkeys. These results suggest that inhalation of KAA-276 would benefit patients with bronchial asthma without inducing unwanted systemic effects.

Administration, Inhalation↗

PubMed2006

Quantitative measurements of regional lung ventilation using helium-3 MRI in a methacholine-induced bronchoconstriction model.

PURPOSE: To demonstrate ventilation changes in an animal model of methacholine-induced bronchoconstriction using hyperpolarized (HP) helium-3 (He-3) MRI. MATERIALS AND METHODS: Bronchoconstriction was induced in 11 healthy rats using an intravenous injection of methacholine. The He-3 was laser-polarized using a custom-built system. MRI studies were performed on a 2-Tesla bore magnet. Coronal dynamic ventilation images were obtained using a single inhalation of the laser-polarized He-3 gas before and after methacholine injection. Ventilation image series were processed on a pixel-by-pixel basis to generate three regional ventilation parameters: gas flow rate, filling time, and maximum gas volume. Student's paired t-test was used for analysis. RESULTS: Ventilation image series with a temporal resolution of 5 msec were obtained before and after methacholine challenge. Quantitative regional gas dynamic information demonstrated statistically significant differences between the baseline and constricted states. Following methacholine injection, the mean flow values were significantly lower for the right lung (RL) (P = 0.006) and left lung (LL) (P = 0.024), while the mean filling time was found to be greater (RL: P = 0.08, LL: P = 0.021). Gas volume values at maximum inspiration were found to be significantly lower after methacholine (RL: P = 0.002; LL: P = 0.036). CONCLUSION: He-3 MRI demonstrated and quantified regional ventilation changes in bronchoconstriction conditions in rats.

Animals↗

PubMed1990

Dose-response relationship of the H1-histamine antagonist, ebastine, against histamine and methacholine-induced bronchoconstriction in patients with asthma.

In a double blind, randomised, placebo controlled trial in a group of extrinsic asthmatics, we have evaluated the potency and selectivity of ebastine, a new piperidine-type H1-receptor antagonist, against histamine and methacholine-induced bronchoconstriction. The median histamine PC20FEV1 value following placebo was 3.15 mg/ml (0.24-58.84). When compared with placebo, ebastine produced significant protection at 10 mg (median PC20 = 31.36 mg/ml, p = 0.008) and 30 mg (median PC20 = 42.14 mg/ml, p = 0.001) but there appeared to be no significant dose effect. Ebastine also produced a small shift in the methacholine concentration-response curves to the right. We conclude that ebastine is an effective antagonist of histamine-induced bronchoconstriction in the asthmatic airway with evidence of minor blockade of methacholine-induced bronchoconstriction.

Adult↗

PubMed1981

Pharmacologic characterization of immune complex induced bronchoconstriction in guinea pigs.

Intravenous injections of soluble immune complexes to anesthetized guinea pigs resulted in bronchoconstriction that was inhibited by FPL 55712, indomethacin, oxarbazole, soybean trypsin inhibitor, and cobra venom factor. Immune complex induced bronchoconstriction was not inhibited by atropine, imidazole, mepyramine, ketotifen, methysergide, and the anti-anaphylactic compound DPP (Diethyl [2-(4-pyridyl)-4-pyrimidinyl]aminoethylene malonate). Immune complex induced bronchoconstriction in guinea pigs appears to involve activation of complement and formation of anaphylatoxins. In addition, products of cyclo-oxygenase metabolism of arachidonic acid and kinins may be involved.

Airway Resistance↗

PubMed1992

Adenosine-induced bronchoconstriction in an allergic rabbit model: antagonism by theophylline aerosol.

Recently, there has been an increasing interest in the involvement of adenosine as a mediator of allergic asthma. In the present study, we have employed an allergic rabbit model to study the airway responses to adenosine. The rabbit litter mates were injected i.p., within 24 h of birth, with ragweed pollen extract to preferentially produce ragweed-specific IgE. This allergic rabbit model demonstrates many clinical features of asthma similar to human allergic asthma. Aerosolized adenosine (0.156-10 mg/ml) caused a concentration-dependent bronchoconstriction. The normal rabbits (non-immunized) did not respond to adenosine within that concentration range. Theophylline significantly inhibited the adenosine-induced bronchoconstriction. These early studies suggest that adenosine differentiated asthmatic airways from normal airways and adenosine-induced bronchoconstriction in this model was mediated through specific cell surface receptor(s).

Adenosine↗

PubMed1979

The effects of captopril (SQ 14,225) on bradykinin-induced bronchoconstriction in the anesthetized guinea pig.

The effect of captopril (SQ 14,225) a potent inhibitor of angiotensin converting enzyme (ACE: kininase II) on the bronchoconstrictor response to bradykinin was studied in the anesthetized guinea pig. The i.v. administration of captopril caused a profound long lasting hypotension without affecting pulmonary resistance or dynamic compliance. Similarly, the i.v. administration of bradykinin caused small increases in pulmonary resistance and decreases in dynamic compliance which were not altered by the administration of captopril. However, after beta-receptor blockade with propranolol, bradykinin-induced changes in resistance and compliance were enhanced; additional captopril administration further potentiated the bradykinin effects. The prostaglandin synthetase inhibitor indomethacin antagonized the bradykinin-induced bronchoconstriction in beta-blocked animals and its potentiation by captopril. In the isolated perfused guinea pig lung, bradykinin caused a dose dependent release of a prostaglandin-like substance which was significantly increased by captopril and antagonized by indomethacin. These results suggest that bradykinin causes a prostaglandin-mediated bronchoconstriction. Captopril, a potent inhibitor of ACE, prevents the degradation of bradykinin thus potentiating the bradykinin-induced bronchoconstriction, an effect observed in intact animals only in the absence of pulmonary beta-receptor activation.

Airway Resistance↗

PubMed1987

A muscarinic receptor with high affinity for pirenzepine mediates vagally induced bronchoconstriction.

The nature of the putative muscarinic receptor subtypes involved in vagally mediated bronchoconstriction was examined in the rabbit model utilizing the classical muscarinic antagonist atropine and the selective antagonist pirenzepine. In vivo electrical stimulation of the cervical vagus nerves in anesthetized rabbits resulted in a reproducible increase in pulmonary resistance indicative of bronchoconstriction and a marked negative chronotropic effect on the heart. Both atropine and pirenzepine produced dose-related inhibition of these two vagal effects. Fifty percent inhibition of the vagally induced increase in pulmonary resistance was achieved with an infusion of pirenzepine that was only 8-fold greater than the equi-effective dose of atropine. In contrast, the dose of pirenzepine required to inhibit the vagally induced decrease in heart rate by 50% was 100-fold greater than the atropine dose. Thus, pirenzepine is markedly more potent in inhibiting vagally mediated bronchoconstriction than bradycardia. In vitro inhibition of methacholine-induced contraction of bronchial rings with atropine and pirenzepine yielded pA2 values of 8.86 and 6.88 respectively (95-fold potency ratio), demonstrating that the muscarinic receptors on airway smooth muscle cells that mediate contraction are not of the pirenzepine-sensitive subtype.

Action Potentials↗

PubMed1989

Doxofylline exerts a prophylactic effect against bronchoconstriction and pleurisy induced by PAF.

The effect of doxofylline, a new xanthine drug with a low incidence of side-effects in the central nervous, renal and gastroenteric system, on the actions of PAF-acether on bronchopulmonary functions was studied. Doxofylline inhibited: (1) PAF-induced bronchoconstriction in vitro, and the concomitant generation of TXA2-like activity in perfused guinea-pig lungs; (2) PAF-induced bronchoconstriction in vivo and the concomitant release of TXA2-like activity into the circulation; (3) PAF-acether-induced pleurisy and the liberation of type C4 leukotriene into the rat pleural cavity. The results suggest that doxofylline, like theophylline, is able to counteract the bronchoconstriction induced by PAF-acether and, in addition, displays anti-inflammatory properties. These pharmacological data support the notion that doxofylline exerts a prophylactic effect against the respiratory damage induced by mediators, such as PAF-acether, of lung bronchial hyperreactivity; its mechanism of action is unusual, it has slight antagonistic activity at A1- and A2-adenosine receptors.

Airway Resistance↗

PubMed1984

Substance P antagonists and the role of tachykinins in non-cholinergic bronchoconstriction.

Electrical field stimulation of guinea-pig isolated hilus bronchi induced tetrodotoxin-sensitive contractions of which only a minor part could be inhibited by atropine. The remaining non-cholinergic bronchoconstriction was antagonized by a heptapeptide and an undecapeptide substance P (SP) analogue (Arg5, D-Trp7,9) SP5-11, IC50 = 24.0 microM and (D-Pro2, D-Trp 7,9) SP, IC50 = 10.0 microM. Of the exogenously added tachykinins, both eledoisin (8 times) and physalaemin (3 times) were more potent bronchoconstrictors than SP. Pretreatment with the SP-analogues shifted concentration-response curves to the tachykinins to the right, eledoisin being most readily antagonized. (Arg5, D-Trp 7,9) SP 5-11 also antagonized the neural response more readily than that of SP. In addition, in the frog isolated sciatic nerve preparation the two SP-analogues were found to possess potent lidocaine-like neurodepressant actions which further complicated the interpretation of the neural inhibitory effects of these compounds. It is concluded that if a tachykinin contributes to non-cholinergic bronchoconstriction, an eledoisin-like peptide is a more likely candidate than SP itself. Since SP-antagonists may have local anaesthetic properties their value as tools in neurophysiology seems limited. Inferentially, the non-cholinergic bronchoconstrictive neurotransmitter remains to be identified.

Animals↗

PubMed1981

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients.

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.

Asthma↗

PubMed1981

Impaired tracheal mucus transport in allergic bronchoconstriction: effect of terbutaline pretreatment.

The transport velocity of mucus within the trachea, pulmonary resistance, and arterial blood gas composition were measured in intubated conscious sheep with Ascaris suum sensitivity before and during allergic bronchoconstriction. Inhalation of A. suum extract for 15 min increased mean pulmonary resistance significantly from 1.9 cm H2O . L-1 sec-1 to 5.1 cm H2O . L-1 sec-1 after 60 min and to 4.5 cm H2O . L-1 sec-1 after 120 min, while it decreased mean arterial PO2 from 85 to 59 and 53 mm Hg, respectively, without altering arterial PCO2 or pH. This was associated with a decrease in mean mucus velocity from 11.2 to 6.0 and 5.7 mm min-1, respectively. The decrease in mucus velocity was accompanied by endoscopically visible increases in the quantity of tracheal mucus. No alterations in mucus velocity or pulmonary resistance were observed in animals who inhaled a control antigen (ragweed) or breathed a mixture of 10% oxygen 90% nitrogen, which produced a mean arterial PO2 of 51 mm Hg. The administration of 0.25 mg terbutaline sulfate by subcutaneous injection prior to A. suum challenge prevented the changes in mucus velocity, pulmonary resistance, and arterial PO2. We conclude that the decreased mucus velocity in the trachea during antigen-induced bronchoconstriction in conscious sheep is related to the allergic response, and can be prevented by the subcutaneous administration of terbutaline sulfate, a beta adrenergic agonists. This suggests that the protective effect of terbutaline sulfate in antigen-induced bronchoconstriction includes the effect on the associated impairment of mucociliary function.

Animals↗

PubMed1984

Respiratory water loss as a stimulus to exercise-induced bronchoconstriction.

Exercise and the resultant hyperpnea increase the magnitude of many stimuli delivered to the airways. Thus clinical "exercise-induced" bronchoconstriction can probably be initiated by a number of stimuli including, for example, sulfur dioxide, which is present in polluted air. In the laboratory, when subjects perform exercise breathing clean air, the water content of the inspired air is a major determinant of the bronchoconstriction induced, whereas in our hands, the temperature of the inspired air is of little or no importance, even over a range associated with significant differences in airway cooling. These observations support the view that water loss is an important stimulus to exercise-induced bronchoconstriction, perhaps as a result of a transient increase in the osmolarity of airway surface liquid.

Asthma↗

PubMed1984

Variable inhibition of histamine-induced bronchoconstriction by atropine in subjects with asthma.

To determine whether treatment with atropine causes dose-dependent inhibition of histamine-induced bronchoconstriction, we constructed dose-response curves to inhaled histamine after inhalation of placebo and 0.26 and 2.08 mg of atropine in eight subjects with mild asthma. Both doses of atropine significantly inhibited histamine-induced bronchoconstriction, and 2.08 mg caused significantly greater inhibition than 0.26 mg. Baseline specific airway resistance was significantly reduced by both doses of atropine but was no different after 2.08 mg than after 0.26 mg. There were considerable differences in the efficacy of atropine among individuals. We conclude that atropine causes dose-dependent inhibition of histamine-induced bronchoconstriction and that this effect is not merely a function of the atropine-induced in baseline airway caliber. The large magnitude of the atropine effect in some subjects and the small magnitude of the effect in others suggest that there is variability in the degree of involvement of muscarinic mechanisms in the exaggerated bronchomotor response to histamine in asthmatic subjects.

Adult↗