Effect of Aerosolized Uridine 5 ′ -Triphosphate on Mucociliary Clearance in Mild Chronic Bronchitis

Abstract

Previous studies show that uridine 5'-triphosphate (UTP), a P2Y(2) receptor agonist, is effective at acutely enhancing mucociliary clearance in healthy, nonsmoking adults. UTP solution for inhalation is being developed by Inspire Pharmaceuticals under the compound number INS316. In a double-blind, randomized, crossover, placebo-controlled study we tested the single-dose effect of UTP in chronic smokers with mild chronic bronchitis (n = 15) by measuring the clearance of (99m)Tc-Fe(2)O(3) particles (4.0 microm mass median aerodynamic diameter [MMAD]) after inhalation of nebulized placebo (0.9% saline) and two doses of UTP (20 and 100 mg in the nebulizer). On each study day, gamma camera scanning was performed over a 2-h period. After an initial deposition scan, subjects inhaled placebo or UTP during the first 20 min of scanning. Analysis of whole lung clearance showed that the retention-time curves for each day were biphasic and that the earliest break point in the average curves occurred at 50 min. Mean particle clearance rate (Clr in %/min) through 50 min for placebo treatment was Clr = 0.65 +/- 0.27 whereas treatment with UTP showed Clr significantly increased to 0.95 +/- 0.48 and 0.93 +/- 0.44 for the 20-mg and 100-mg dose respectively, p < 0.005 for both as compared with placebo. These data show that mucociliary clearance associated with mild chronic bronchitis is acutely improved with minimal doses of aerosolized UTP, presumably because of its stimulation of ciliary beating and hydration of airway secretions.

Epithelial Mucus-Hypersecretion and Respiratory Disease

“…The significance of these responses has been confirmed in the clinic using exogenously applied P2Y 2 receptor agonists. Aerosol exposure to these compounds resulted in increased clearance of 99 Tc labelled iron oxide from the lungs of healthy smokers/mild chronic bronchitics [59]. Inhalation of noxious gases also has the effect of acutely accelerating mucociliary clearance in man [60][61][62] and similar changes have been observed in pre-clinical models.…”

New concepts of the pathogenesis of cystic fibrosis lung disease

“…It appears from studies of both purinoceptor agonists and hypertonic saline that this phenomenon does occur, but is transient, i.e. f30 min [109,110].…”

Role of mechanical stress in regulating airway surface hydration and mucus clearance rates

“…It should be pointed out, as discussed below, that the increase in Ca 2+ i by activation of P2Y 2 receptors can modulate the activity of other cellular processes in addition to changes in ion transport, including activation of mucin secretion (Lethem et al, 1993) and increasing the rate of ciliary beating (Yoshitsugu et al, 1993;Winters et al, 2007). Importantly, studies have demonstrated that the net result of this activation by exogenous luminal ATP is an increased mucus clearance rates (Bennett et al, 2001). …”