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Biomedical subjects

J Morley

Publications and source records attributed to J Morley.

At least 91 records · Page 5Linked to original sources
PubMed1991

Airway eosinophilia and airway hyperreactivity are parallel rather than sequential events in the guinea-pig.

It is known that eosinophil activation in the airways is associated with epithelial damage in both guinea-pigs and man and it has been presumed that airway hyperreactivity arises in consequence of these events. However, infusion of (+/- )isoprenaline induces airway hyperreactivity in the guinea-pig despite a reduction of eosinophil numbers in the airway lumen, whilst rh-GM-CSF or rh-IL3 induce eosinophilia of the airways without attendant airway hyperreactivity. These findings complement earlier studies which showed that airway hyperreactivity in sensitized animals reacting to inhaled allergen could not be correlated with the number of eosinophils in the airway lumen.

Allergens↗
PubMed1991

Actions of SDZ PCO 400 and cromakalim on airway smooth muscle in vivo.

SDZ PCO 400, and cromakalim are potassium channel opening drugs which relax airway smooth muscle and reverse airway obstruction due to intravenous administration of airway spasmogens. Reduction of airway obstruction by these drugs may be attributed to actions upon airway reactivity as well as airway smooth muscle spasmolysis; for, at concentrations which do not induce overt relaxation of airway smooth muscle, both SDZ PCO 400 and cromakalim suppressed development of airway hyperreactivity due to administration of immune complexes, PAF or (+/-)isoprenaline and reversed established airway hyperreactivity due to allergic reactions. When administered as aerosols prior to inhalation of allergen in actively sensitized guinea-pigs, or by the oral route in guinea-pigs with idiopathic eosinophilia, neither cromakalim nor SDZ PCO 400 influenced the influx of eosinophils into the airway lumen. Thus, SDZ PCO 400 and cromakalim may readily be distinguished from established prophylactic anti-asthma drugs such as cromoglicate and ketotifen. By influencing airway reactivity, potassium channel openers provide a novel approach to the resolution of airway obstruction in asthma.

Animals↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1989

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↗
PubMed1989

A placebo-controlled, double-blind crossover study of naltrexone hydrochloride in outpatients with normal weight bulimia.

The endogenous opioid system plays an important role in the control of feeding behavior. Previous research has shown that antagonism of endogenous opioids will suppress feeding in certain models in both human and infrahuman species. In the current study, 16 normal-weight bulimic women were treated with low-dose naltrexone, the long-acting, orally active narcotic antagonist, and placebo in a crossover design. The use of the active drug was not associated with a clinically significant reduction in binge eating or vomiting episodes. Suggestions for further research in this area are offered.

Adult↗
PubMed1989

Asthma pharmacology: industrial/clinical interface.

The disease of asthma remains poorly understood. Hence, considerable latitude has been afforded to pharmacologists concerned to identify novel compounds for development as anti-asthma drugs. Compounds can be selected (1) on the basis of known efficacy as bronchodilator (beta-adrenoceptor agonists, parasympatholytics and xanthines) and prophylactic (cromoglycate and ketotifen) or anti-inflammatory (glucocorticosteroids) actions; (2) by reference to current theories of asthma pathogenesis, e.g., inhibition of the formation and action of autoacoids (leukotrienes, platelet-activating factor) or cytokines (GM-CSF, IL-5), or (3) by reference to hitherto unexplored physiological processes (K+ channel activation, PDE isoenzyme inhibition, selective immunosuppressive actions). There is a need to test whether the rationale for drug selection is justified. This can only be resolved by study of asthma patients, since normal subjects may respond inappropriately. Thus, normal subjects do not exhibit airway obstruction or airway hyperreactivity and hence do not respond to bronchodilator substances. Similarly, normal subjects respond to platelet-activating factor with a cellular infiltrate in which neutrophils predominate in contrast to atopic asthmatics who exhibit an eosinophilia. It follows that compound discovery and evaluation must be an iterative procedure in which animal studies are supplemented by clinical studies and vice versa. This is most readily achieved by establishing clinical research that is a complementary to preclinical research.

Asthma↗