Comparison of the effects of UTP and 5 '-AMP on guinea-pig lung function and airways mucus secretion [Abstract]

Uridine triphosphate (UTP)1 and adenosine2 stimulate P2Y2 and P1 receptors, respectively, located on lung goblet cells,their activation promoting mucus secretion. We compared inhaled UTP and 5’-AMP on mucus secretion and airways function in an in vivo mucus hypersecretory phenotype model. Male Dunkin-Hartley guinea-pigs (200–250 g) were sensitised with ovalbumin (OA 100μg) and Al(OH)3 (100 mg i.p.) on days 1 and 5. Guinea-pigs received nebulised OA (60 min 0.01%) on day 15, and 0.1% on days 17, 19, 21, 23, 25, 27 and 29, with mepyramine maleate (30 mg/kg ip) 1 hr prior to OA challenge on days 17–27. On day 30, guinea-pigs (n=6) received: nebulised UTP (1 or 10 mM/15mins); UTP 30mins following suramin hexasodium (60 mg/kg ip); 5’-AMP (3 mM for 1 min) or vehicle. Whole body plethysmography measured specific airway conductance (sGaw) before and following UTP or 5’-AMP. Guinea-pigs were then anaesthetic overdosed, lungs removed, inflated with formaldehyde (1 ml/100 g), fixed and embedded in paraffin wax. Sections (3 μm) were stained with alcian blue/periodic acid-Schiff (AB/PAS). Area of AB/PAS-stained mucin-positive epithelium was expressed as % total epithelial area measured with SigmaScan Image Analysis program. UTP (1 and 10 mM) gradually reduced sGaw, reaching −29.77±8.70 and −27.2±2.4% after 60 min. AB/PAS-positive epithelium was significantly reduced from 30.1±5.7% after vehicle to 9.5±2.0% and 16.5±2.8%, indicating mucin release, which suramin blocked. No mucin loss occurred at 0 h (24.4±4.0%) compared to vehicle (24.3±2.8%), significant reduction at 1 h (12.1±2.7%) and partial recovery at 48 h (18.9±2.7%). 5’-AMP caused no immediate changes in sGaw; OA challenges had presumably degranulated mast cells. At 5 h there was a late bronchoconstriction (peak sGaw fall −31.5±5.2%) lasting 24 h. AB/PAS-positive epithelium was significantly reduced from 47.06±3.95% to 30.5±4.2% by 5’-AMP challenge. Thus, P1 and P2Y2 receptor stimulation release mucus, the latter accompanied by airways function changes