The effects of drugs on Sephadex-induced eosinophilia and lung hyper-responsiveness in the rat.
1. Rats given an intravenous injection of Sephadex particles (0.5 mg of G200 in 1 ml of saline) on days 0, 2 and 5 had a blood eosinophilia which was maximal on day 7. 2. On day 7, broncho-alveolar lavage (BAL) fluids taken from the rats contained an increased number of eosinophils and fewer mononuclear cells but there was no change in the small number of neutrophils. In addition the rats were hyper-sensitive to the increase in resistance to artificial respiration produced by 5-hydroxytryptamine (5-HT), given intravenously, with a shift to the left of the log dose-response curve. Lung parenchymal strips, taken from the rats on days 6, 7 and 8, were hyper-reactive to 5-HT with an increase in slope of the log dose-response curve. 3. Compounds with a wide variety of activities were evaluated for their effects on the blood eosinophilia on day 7 when given before each injection of Sephadex. The eosinophilia was reduced by glucocorticosteroids, beta-adrenoceptor agonists, aminophylline, dapsone and phenidone. 4. Dexamethasone, isoprenaline, dapsone and phenidone at doses that reduced the blood eosinophilia also reduced the changes in number of leucocytes in the BAL fluids and the hyper-responsiveness to 5-HT in vivo and in vitro, except that the effects of dapsone on the hyper-sensitivity to 5-HT in vivo did not reach significance. Aminophylline was the least effective of the drugs at reducing the blood eosinophilia and its effects on the other changes did not reach significance. Sodium cromoglycate reduced the BAL eosinophilia but had no effect on the other changes produced by Sephadex. 5. The correlation coefficients between blood eosinophil numbers and reactivity to 5-HT in vitro and sensitivity in vivo were r = 0.76, (n = 88; P < 0.001) and r = 0.53, (n = 61; P < 0.001) respectively. 6. Doses of dexamethasone, isoprenaline, dapsone and phenidone that reduced the blood eosinophilia when given before each injection of Sephadex were inactive when given up to 8 h after the Sephadex. 7. These data show an association between blood eosinophilia and hyper-responsiveness of the lung. The blood eosinophilia in the rats was triggered within the first few hours of injecting the Sephadex and drugs have been identified which inhibit this trigger.
Spicer
B A
BA
SmithKline Beecham Pharmaceuticals, Epsom, Surrey.
Baker
R C
RC
Hatt
P A
PA
Laycock
S M
SM
Smith
H
H
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D003911:Dextrans; D004802:Eosinophilia / Q000097:blood* / Q000139:chemically induced / Q000517:prevention & control; D066298:In Vitro Techniques; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects; D008171:Lung Diseases / Q000139:chemically induced* / Q000503:physiopathology; D009504:Neutrophils / Q000187:drug effects; D010316:Particle Size; D051381:Rats; D011919:Rats, Inbred Strains; D012121:Respiration, Artificial; D012701:Serotonin / Q000494:pharmacology
D003911:Dextrans; D012701:Serotonin; C025614:sephadex