Inhibition of natural anti-inflammatory mechanism by beta 2-agonists.
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Adrenergic beta-Agonists↗
Biomedical subjects
S Sanjar
Publications and source records attributed to S Sanjar.
Measurement and pharmacology of mucociliary clearance.
Airways mucociliary clearance (MCC), which continuously removes inhaled particles and cellular debris from the lungs is impaired in a number of diseases such as bronchitis, asthma and cystic fibrosis. Regulation of MCC under normal conditions is not well understood and the cause of its impairment is ill defined. Animal models have been used to study the regulatory mechanisms of both mucus secretion and MCC and to ascertain the involvement of neural pathways. Cholinergic stimulation is a most effective means of enhancing MCC in molluscs, frogs and mammals including man. Recent data from mammals suggest that MCC is also regulated by neuropeptides either directly (substance P) or by facilitating the stimulatory effect of cholinergic agents. A better understand of basic regulatory mechanisms of MCC is vital to an understanding of its impairment in respiratory diseases.
Animals↗
Antigen challenge induces pulmonary airway eosinophil accumulation and airway hyperreactivity in sensitized guinea-pigs: the effect of anti-asthma drugs.
1. Guinea-pigs were sensitized with 3 injections of ovalbumin (OA) (1 or 10 micrograms per animal) using Al(OH)3 and pertussis vaccine as adjuvants at two week intervals. 2. Sensitized guinea-pigs were challenged with an aerosol of OA (0.1%) over a one hour period and both airway reactivity and cellular content of bronchoalveolar lavage (BAL) fluid were assessed at intervals for up to 7 days. 3. Guinea-pigs sensitized with 1 microgram of ovalbumin responded to an aerosol of OA with increased pulmonary airway eosinophilia, which was evident 1 day after challenge and was present for up to 7 days. Airway hyperreactivity was not detectable in these animals. 4. Guinea-pigs sensitized with 10 micrograms of ovalbumin responded to an aerosol of OA with increased pulmonary airway neutrophilia and eosinophilia and with increased airway reactivity which was maximal between 8 and 24 h after exposure to OA. 5. Depletion of circulating platelets or neutrophils, by use of selective antisera, did not alter either the magnitude of eosinophilia or the intensity of airway reactivity in sensitized guinea-pigs (10 micrograms) exposed to an aerosol of OA. 6. Pretreatment of sensitized guinea-pigs (10 micrograms) for 6 days with AH 21-132, aminophylline, dexamethasone or ketotifen inhibited pulmonary airway eosinophilia, but did not diminish airway hyperreactivity. Neither eosinophil accumulation nor development of airway hyperreactivity was influenced by treatment with mepyramine or salbutamol over a 6 day period before OA inhalation. 7. Although eosinophilia may occur in association with increased airway reactivity in this animal model, there is no evidence of a causal relationship.
Animals↗
Eosinophil accumulation in pulmonary airways of guinea-pigs induced by exposure to an aerosol of platelet-activating factor: effect of anti-asthma drugs.
1. Exposure of guinea-pigs to aerosols of platelet activating factor (PAF) (0.01 to 100 micrograms ml-1) induced a dose-dependent increased incidence of eosinophils in bronchoalveolar lavage fluid (BAL) at 48 h. Total leucocyte numbers and the percentages of lymphocytes and neutrophils were unchanged in BAL fluid. 2. Increased numbers of eosinophils were detected in BAL 1 h after exposure to PAF but eosinophilia was not maximal until 48 h. One week after exposure to PAF, the percentage of eosinophils in BAL was within the normal range. 3. Depletion of circulating platelets or neutrophils by intravenous injection of specific antisera did not modify accumulation of eosinophils in the airway lumen following inhalation of PAF (10 micrograms ml-1). 4. PAF-induced pulmonary airway eosinophil accumulation was inhibited by treatment with SDZ 64-412, a selective PAF-antagonist, whether the compound was administered before, or 30 min after, inhalation of PAF. 5. Pulmonary airway eosinophil accumulation due to inhaled PAF (10 micrograms ml-1) was inhibited by prior treatment with aminophylline, cromoglycate, ketotifen, dexamethasone and AH 21-132. 6. Pulmonary airway eosinophil accumulation due to inhaled PAF (10 micrograms ml-1) was not inhibited by prior treatment with indomethacin, salbutamol or mepyramine.
Aerosols↗
Pretreatment with rh-GMCSF, but not rh-IL3, enhances PAF-induced eosinophil accumulation in guinea-pig airways.
Intraperitoneal injections of recombinant human granulocyte-macrophage colony stimulating factor (rh-GMCSF, 50 micrograms/kg-1 daily) or interleukin-3 (rh-IL3, 50 micrograms kg-1 daily) for two days, induced an increase in the percentage of bone marrow and pulmonary airway eosinophils in the guinea-pig. In addition, rh-IL3-treated animals exhibited an increase (21%) in blood neutrophils. Exposure of guinea-pigs to an aerosol of platelet activating factor (PAF) gives rise to a selective pulmonary eosinophil accumulation, maximal at 48 h. The eosinophilic response to PAF was significantly enhanced in rh-GMCSF-treated guinea-pigs but was suppressed in rh-IL3-treated animals.
Aerosols↗
Increased airway reactivity in the guinea-pig follows exposure to intravenous isoprenaline.
1. Intravenous infusion of (+/-) isoprenaline (1-100 micrograms kg-1 h-1) enhanced airway responses (resistance, RL; and compliance, Cdyn) to histamine (1.0-1.8 micrograms kg-1) and bombesin (100-240 ng kg-1), whereas airway responses to vagal stimulation remained unchanged. 2. Bilateral vagotomy before intravenous infusion of (+/-)isoprenaline (100 micrograms kg-1 h-1) prevented development of airway hyperreactivity to histamine or bombesin, yet vagotomy after infusion of isoprenaline was without effect. 3. Prior treatment with atropine (1 mg kg-1) did not influence the capacity of (+/-)isoprenaline (100 micrograms kg-1 h-1) to increase airway reactivity to bombesin. 4. Despite a 500-fold difference in spasmolytic potency in vivo, infusion of (+)isoprenaline (100 micrograms kg-1 h-1) or (-)isoprenaline (100 micrograms kg-1 h-1) increased reactivity of the airways to histamine or bombesin to a comparable extent. 5. Neither adrenaline (100 micrograms kg-1 h-1) nor forskolin (600 micrograms kg-1 h-1) increased reactivity of the airways to histamine or bombesin. 6. Intravenous infusion of dopamine (100 micrograms kg-1 h-1) or noradrenaline (100 micrograms kg-1 h-1) increased reactivity of the airways to histamine or bombesin. 7. Intravenous infusion of (+/-) propranolol (100 micrograms kg-1 h-1) increased reactivity of the airways to histamine or bombesin which was partially inhibited by bilateral vagal section. 8. Depletion of circulating platelets by lytic anti-platelet serum or concomitant infusion of an antagonist of platelet-activating factor (PAF), ginkgolide B (1 mg kg-1 h-1) did not diminish the capacity of (+/-)isoprenaline (100 micrograms kg-1 h-1) to induce hyperreactivity of the airways to histamine or bombesin. 9. These observations indicate that (+/-)isoprenaline can induce airway hyper-reactivity by a mechanism unrelated to beta-adrenoceptor activation, but which is dependent upon intact vagus nerves.
Airway Resistance↗
Human recombinant lymphokines and cytokines induce pulmonary eosinophilia in the guinea pig which is inhibited by ketotifen and AH 21-132.
Subcutaneous or intraperitoneal injection of recombinant human granulocyte-macrophage colony-stimulating factor, interleukin 3, or mouse tumour necrosis factor alpha, but not recombinant human interferon gamma, platelet-derived growth factor, or transforming growth factor beta caused selective eosinophilia of the pulmonary airways in the guinea pig. Unlike responses to platelet-activating factor, there was no attendant detectable airway hyperreactivity, but in common with responses to platelet-activating factor, eosinophilia of the airways was prevented by pretreatment with ketotifen or AH21-132. Cytokines or lymphokines may contribute to pulmonary eosinophilia in diseases such as asthma.
Airway Resistance↗
Evidence that neutrophils do not participate in the late-phase airway response provoked by ovalbumin inhalation in conscious, sensitized guinea pigs.
Inhalation of ovalbumin by conscious, sensitized guinea pigs induced two phases of airway obstruction measured at 2 h (EAR) and at 17 h (LAR), respectively. In addition to causing airway obstruction, allergen challenge induced an accumulation in the bronchial lumen of eosinophil and neutrophil polymorphonuclear leukocytes at 17 h. Intraperitoneal injection of guinea pigs with a specific rabbit anti-guinea pig neutrophil serum 24 h before challenge reduced the number of circulating neutrophils by 94% and the airway neutrophilia after challenge by 90%, but it had no effect on the magnitude of either the EAR or the LAR. The observation that the LAR was not effected by neutropenia supports previous conclusions derived from experiments using the anti-allergic drugs, cromolyn sodium and nedocromil sodium, and the beta 2-adrenoceptor stimulant, albuterol, that, although there is a temporal relationship between neutrophil accumulation in the airways and the peak of the LAR, this polymorphonuclear leukocyte does not play a central role in the pathophysiologic processes that give rise to the late-phase response to guinea pig airways.
Administration, Inhalation↗
Viewpoint: untoward effects of beta-adrenoceptor agonists in asthma.
Beta-adrenoceptor agonists are potent and selective relaxants of airway smooth muscle. They produce symptomatic bronchodilatory effects and are the most widely used therapy in asthma. In patients with asthma, they usually effect a reduction of airway resistance, but there have been several reports of episodes of increased airway obstruction, arterial hypoxaemia and even death associated with such therapy. "Anomalous or paradoxical bronchospasm" are appropriate terminologies to describe this unexpected phenomenon. Five mechanisms have been proposed to account for anomalous responses to these substances: 1) reactive myogenic tone; 2) metabolic products with spasmogenic activity; 3) adrenoceptor tachyphylaxis; 4) increased inflammatory burden; and 5) induction of airway hyperreactivity. Following a review of the relative merits of each proposal, it is concluded that increased inflammatory burden and induction of airway hyperreactivity, alone or in combination, provide the most plausible explanation for paradoxical bronchospasm.
Adrenergic beta-Agonists↗
In vivo method for the assessment of platelet accumulation.
Platelets labeled with 111Indium have been injected intravenously into anesthetised guinea pigs, and intrathoracic content of 111Indium-labeled platelets has been monitored continuously using a microcomputer-based system (AIMSplus). Dose-effect relationships have been described for ADP, collagen, and PAF, and effects of drugs upon selected responses illustrate the potential of this test system for routine in vivo screening of agents that may inhibit aggregation of platelets.
Adenosine Diphosphate↗
The effect of prophylactic anti-asthma drugs on PAF-induced airway hyperreactivity.
Intravenous injection of platelet activating factor (PAF) in anesthetized guinea pigs induces non-selective airway hyperreactivity. This response to PAF was reduced in a dose-dependent manner by systemic administration of established prophylactic anti-asthma drugs (ketotifen, cromoglycate, aminophylline and glucocorticosteroids) and by competitive antagonists of PAF. These inhibitory effects could not be accounted for by antagonism of histamine (H1), serotonin or peptidoleukotrienes receptors; parasympatholytic activity; cyclo-oxygenase or lipoxygenase inhibition; mast cell stabilization; or bronchodilatation. Infusion or injection of PAF to induce airway hyperreactivity in the guinea pig may provide a prospective test for prophylactic anti-asthma drugs.
Animals↗
The effect of prophylactic anti-asthma drugs on PAF-induced platelet accumulation in the thorax of the guinea pig.
Intravenous infusion of platelet activating factor (PAF) causes an accumulation of platelets within the thorax of the guinea pig that is accompanied by increased sensitivity of the airways to spasmogens. A crystal scintillation detector has been used for measurement of intrathoracic accumulation of 111Indium-labeled platelets during responses to PAF. PAF-antagonists inhibit development of airway hyperreactivity, do not diminish platelet accumulation in response to an intravenous infusion of PAF. It is therefore concluded that intrathoracic platelet accumulation per se is not the determinant of increased airway reactivity.
Airway Resistance↗
Inhibition of PAF-induced eosinophil accumulation in pulmonary airways of guinea pigs by anti-asthma drugs.
Intraperitoneal (i.p.) injection of platelet activating factor (PAF) in guinea pigs caused a dose-related increase in the number of eosinophils recovered from bronchoalveolar lavage fluid (BALF). The prevalence of eosinophils in BALF had significantly increased within 1 hr of i.p. injection of PAF (10 micrograms/animal) and was maximal after 24 hr. Subcutaneous osmotic mini-pumps were used to administer drugs for 5 days prior to i.p. injection of PAF (10 micrograms/animal) and for the subsequent 24 hr. The percentage increase of eosinophils in BALF, due to PAF, was inhibited in animals treated with dexamethasone, aminophylline, cromoglycate, tranilast or ketotifen, but not in animals treated with oxatomide, azelastine, amlexanox, ibudilast or AA-861. These results suggest that inhibition of pulmonary eosinophilia may be a necessary property of prophylactic anti-asthma drugs and provide indirect evidence favoring a role for PAF in eosinophilia of asthma.
Animals↗
Airway hyperreactivity.
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Airway Resistance↗
Pharmacological evaluation of prophylactic anti-asthma drugs by reference to the pathological sequelae of exposure to allergen or platelet activating factor.
Exposure of guinea-pigs to platelet activating factor (PAF) induces airway hyperreactivity and causes an influx of eosinophils into the airways. These effects are inhibited by the established prophylactic anti-asthma drugs; cromoglycate, aminophylline, glucocorticosteroids and ketotifen, whereas other drug categories, with the exception of PAF-receptor antagonists, are ineffective.
Allergens↗
Pharmacology of ketotifen in asthma.
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Asthma↗