This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Triphosphate nucleotides such as uridine 5'-triphosphate (UTP) regulate specific activities of human airway epithelial cells that comprise the mucociliary escalator, a lung defense mechanism that serves to transport foreign particles out of the lungs. The mucociliary escalator relies on the integrated actions of: 1) mucus secretion by goblet cells and submucosal glands to trap foreign particles; 2) cilia to propel the mucus out of the lungs; and 3) epithelial ion transport systems that maintain the ionic milieu of airway surface liquid to allow effective ciliary beating. Triphosphate nucleotides mediate these actions by interacting with specific cell surface receptors (P2Y2) on the airway epithelia. INS37217, a new P2Y2 agonist, also produces these actions via activation of P2Y2 receptors. More recent research shows that P2Y2 agonists inhibit Na+ transport across human airway epithelia. The actions of the mucociliary escalator system are impaired in various obstructive lung diseases, such as cystic fibrosis (CF), which are characterized by increased amounts of thickened mucus. Patients with these disorders have difficulty in clearing the thickened mucus from the airways, which eventually results in chronic obstructive changes, repeated pulmonary infections, and eventually death. Current therapies for CF lung disease focus either on attempts to change the consistency of mucus or treat the bacterial infection, including selective agents against P. aeruginosa. Dornase alfa (Pulmozyme) Inhalation Solution has been demonstrated to be beneficial by reducing viscosity of respiratory secretions. In clinical trials, Pulmozyme was shown to reduce the frequency of pulmonary exacerbations and improve lung function. Inhaled tobramycin (TOBI) has been shown to reduce the frequency of hospitalization, improve lung function, and reduce the P. aeruginosa content in sputum. Although both products are beneficial, neither is targeted at the basic ionic transport defect, which is the underlying cause of the pulmonary manifestations of basic CF. Since the pulmonary manifestation of CF is related to the impairment of salt and fluid transport in respiratory epithelia, a product aimed at correcting this defect could have significant clinical benefit for CF patients. A key discovery in the early 1990's demonstrated that triphosphate nucleotides such as adenosine 5'-triphosphate (ATP) and uridine 5'- triphosphate (UTP) activate chloride secretion in normal and CF airway epithelia. The Cl- secretory response was initiated via a rise in intracellular Ca2+ activated Cl- channel. This stimulated chloride transport, coupled with an inhibitor of Na+ transport and was associated with increased liquid transport across the apical surface. This physiologic response is known to be mediated via specific 'purinergic receptors', known as the P2Y2 receptors. Therapies designed to normalize airway surface liquid composition and volume are highly desired. Since P2Y2 receptor agonists have the potential for correcting the fundamental pulmonary defect of CF patients, it is thought that P2Y2 agonists such as INS37217, by improving ciliary beat frequency and increasing hydration in airways, will improve mucociliary clearance and thereby provide clinical benefits to patients with these disorders.
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