L M Spruntulis1, K J Broadley. 1. Pharmacology Department, Welsh School of Pharmacy, Cardiff University, Cardiff, UK.
Abstract
BACKGROUND: Inhaled adenosine causes bronchoconstriction in asthmatics and may modulate inflammatory cell activity. Elevated adenosine levels occur in the lungs after antigen challenge of asthmatics. OBJECTIVES: The aim of this study was to investigate whether the bronchoconstrictor effects of the adenosine derivative, 5'-AMP, were associated with altered migration of inflammatory cells into the airways using a sensitized atopic guinea-pig model previously shown to display a bronchoconstrictor response. Comparisons were made with the effects of inhaled antigen. METHODS: Airway responses of conscious sensitized guinea-pigs to inhalation exposures of 5'-AMP were determined by whole body plethysmography as the change in specific airway conductance (sGaw). Influx of leucocytes into the airways was determined by bronchoalveolar lavage (BAL). RESULTS: 5'-AMP caused bronchoconstrictor airway responses in sensitized animals. Dose-dependent infiltration of inflammatory cells into the lungs occurred 1 h after 5'-AMP exposure. No bronchoconstriction or cell influx was seen in unsensitized guinea-pigs. Exposure to ovalbumin (OA) also caused influx of inflammatory cells. Twenty-four hours after an OA exposure, 5'-AMP produced no bronchoconstriction. The P1-receptor antagonists, 8-PT and 8-SPT, inhibited the 5'-AMP-induced bronchoconstriction, indicating that the bronchoconstriction seen in sensitized animals is mediated by A1 or A2 receptors. They had no effect on the cell influx, whereas the A3 antagonist, MRS-1220, significantly inhibited cellular infiltration, suggesting mediation through A3 receptors. At 24 h after an OA challenge and accompanying the cellular influx, there was airway hyper-responsiveness to the bronchoconstriction by histamine. In contrast, no hyper-responsiveness to histamine was seen 1 h after 3 mM or 24 h after 300 mM 5'-AMP. CONCLUSIONS: 5'-AMP caused a rapid migration of eosinophils and macrophages into the airways only in sensitized guinea-pigs, and this was blocked by the A3 antagonist MRS-1220. This was not associated with bronchial hyper-reactivity to histamine.
BACKGROUND: Inhaled adenosine causes bronchoconstriction in asthmatics and may modulate inflammatory cell activity. Elevated adenosine levels occur in the lungs after antigen challenge of asthmatics. OBJECTIVES: The aim of this study was to investigate whether the bronchoconstrictor effects of the adenosine derivative, 5'-AMP, were associated with altered migration of inflammatory cells into the airways using a sensitized atopic guinea-pig model previously shown to display a bronchoconstrictor response. Comparisons were made with the effects of inhaled antigen. METHODS: Airway responses of conscious sensitized guinea-pigs to inhalation exposures of 5'-AMP were determined by whole body plethysmography as the change in specific airway conductance (sGaw). Influx of leucocytes into the airways was determined by bronchoalveolar lavage (BAL). RESULTS:5'-AMP caused bronchoconstrictor airway responses in sensitized animals. Dose-dependent infiltration of inflammatory cells into the lungs occurred 1 h after 5'-AMP exposure. No bronchoconstriction or cell influx was seen in unsensitized guinea-pigs. Exposure to ovalbumin (OA) also caused influx of inflammatory cells. Twenty-four hours after an OA exposure, 5'-AMP produced no bronchoconstriction. The P1-receptor antagonists, 8-PT and 8-SPT, inhibited the 5'-AMP-induced bronchoconstriction, indicating that the bronchoconstriction seen in sensitized animals is mediated by A1 or A2 receptors. They had no effect on the cell influx, whereas the A3 antagonist, MRS-1220, significantly inhibited cellular infiltration, suggesting mediation through A3 receptors. At 24 h after an OA challenge and accompanying the cellular influx, there was airway hyper-responsiveness to the bronchoconstriction by histamine. In contrast, no hyper-responsiveness to histamine was seen 1 h after 3 mM or 24 h after 300 mM 5'-AMP. CONCLUSIONS:5'-AMP caused a rapid migration of eosinophils and macrophages into the airways only in sensitized guinea-pigs, and this was blocked by the A3 antagonist MRS-1220. This was not associated with bronchial hyper-reactivity to histamine.