Airway hyper‐ or hyporeactivity to inhaled spasmogens 24 h after ovalbumin challenge of sensitized guinea‐pigs

Abstract

1 The aim of this study was to determine whether an inhalation of ovalbumin (OA, 10 or 20 mg ml-') by conscious OA-sensitized guinea-pigs leads to airway hyperreactivity to spasmogens 24 h later. In contrast to most previous studies, the spasmogens (5-HT, methacholine (MCh), U-46619 and adenosine) were administered by inhalation and airway function was measured in conscious guinea-pigs. 2 Guinea-pigs were sensitized by i.p. injection of 10 jg OA and 100 mg aluminium hydroxide in 1 ml normal saline; 14-21 days later they were exposed to an inhalation of 5-HT, MCh, U-46619 or adenosine. Specific airway conductance (sGaw) was measured in conscious animals by whole body plethysmography. The spasmogens caused bronchoconstriction, measured as a reduction in sGaw from the pre-inhalation basal values. Dose-related bronchoconstrictions were observed with 5-HT, MCh and U-46619. 3 The effect of an ovalbumin macroshock challenge upon the responses to each spasmogen were examined by giving an inhalation of aerosolized OA at 24 h (or 7 days in the case of adenosine) after an initial spasmogen challenge. Eighteen to twenty-four hours after the OA macroshock, the same guineapigs were exposed to a repeated inhalation of 5-HT, MCh, U-46619 or adenosine. 4 U-46619 was the only spasmogen to demonstrate hyperresponsiveness, the peak change in sGaw being increased from -12.3 + 9.9 to -38.8 + 5.0% by 10 mg ml-' OA challenge. In contrast, the ovalbumin challenge (20 mg ml-') inhibited the bronchoconstrictions to 5-HT (50 jg ml-') and MCh (100 jig ml-'). Adenosine demonstrated bronchoconstriction in sensitized guinea-pigs but no significant change in the response was observed after an OA challenge. 5 All results were compared with a control group of sensitized guinea-pigs receiving a NaCl challenge. The bronchoconstrictor responses to 5-HT, MCh, U-46619 or adenosine did not differ significantly before and after the saline challenge, indicating reproducibility of the responses. 6 In further experiments, guinea-pigs were exposed to inhalation of 5-HT (50 jg ml-') or MCh (300 jg ml-') 24 h before atropine (10 jig, 100 jg or 1 mg ml-') and again at 0.5 to 1.5 h afterwards. Atropine antagonized the 5-HT-and MCh-induced bronchoconstrictions over the same antagonist doserange. This suggests that the bronchoconstriction induced in the conscious guinea-pig by 5-HT is mediated primarily via muscarinic receptors, possibly by a vagal reflex. The inhibition of the responses to 5-HT and MCh by OA challenge would therefore appear to be related to interference with a common cholinergic pathway for these spasmogens. 7 In summary, airway hyperresponsiveness was evident at 24 h after OA challenge as measured by an enhanced bronchoconstrictor response to inhaled U-46619. When 5-HT or MCh were used as the spasmogens, an opposing decrease in responsiveness was observed. This was presumed to be due to an inhibition of cholinergic pathways by the OA challenge. Adenosine caused a bronchoconstriction in the sensitized animals but this was not enhanced by the OA ...

Temporal relationships between leukocytes, IL-5 and IL-8 in guinea pig lungs, plasma cortisol and airway function after antigen challenge

“…An earlier development of hyperresponsiveness was not investigated because the baseline bronchoconstriction was still evident following the early phase which could have influenced the responsiveness to U46619. The use of U46619 arises from our earlier studies in which, although it yields a short lasting response, this spasmogen revealed the greatest degree of hyperresponsiveness [5].…”

“…Airway function of the conscious animals was recorded as described above at 2, 5, 10 and 20 min following U46619 exposure. This has previously been found to be a threshold dose for a small bronchoconstriction [5].…”

“…Administering inhaled antigen to the sensitised animal can lead to the development of a number of features in common with bronchial asthma including: early and late phase bronchoconstrictor responses, inflammatory cell recruitment and the development of airway hyperreactivity [2][3][4][5][6][7]. Knowledge of the mechanisms underlying these inflammatory events in guinea pigs is growing with development of cytokine-specific antagonists [8][9][10][11][12][13] and the use of antibodies directed against several of the cellular adhesion molecules [14][15][16].…”

“…We have previously demonstrated airway hyperreactivity to the inhaled thromboxane-mimetic U46619 in conscious, sensitised guinea pigs at the time of the development of a late phase response to inhaled antigen [5,20]. Others have also demonstrated airway hyperreactivity at the time of the late phase [21] and there are studies which show AHR as early as 1 h after the antigen challenge [2].…”

¹¹¹In–Labelled Leukocyte Migration to the Lungs of Ovalbumin–Sensitized Guinea–Pigs after Aerosol Challenge with Ovalbumin Monitored by Gamma Scintigraphy

“…This is associated with bronchial hyperresponsiveness to a number of spasmogens [5, 6]and the development of early– and late–phase bronchoconstrictor response in subjects with atopic asthma [7, 8, 9]and in ovalbumin (OA)–sensitized guinea pigs [1, 10]. In the present study, we utilize a method for injecting radiolabelled leukocytes into anaesthetized guinea–pigs to examine their migration to the lungs after antigen challenge.…”