부산대학교 도서관

In this study, we demonstrate a novel regulatory mechanism by which mucosal nucleotides via P2Y receptors decrease paracellular Cl.sup.- ion permeability in natural rabbit airway epithelium (in addition to a decrease in active Na.sup.+ absorption). In contrast to primary cultures, the natural airway epithelium is a low-resistance epithelium, and an equivalent circuit model predicts that changes of more than [proportional to]12% in transepithelial conductance (G .sub.t) must include an effect on paracellular conductance (G .sub.s). Mucosal P2Y receptor stimulation with uridine triphosphate (UTP 200 uM) decreased G .sub.t by up to 50% (average, 24%) and simultaneously decreased the paracellular Cl.sup.- permeability (mucosa-to-serosa Cl.sup.- flux) by 16%, but had no effect on mannitol permeability. The G .sub.t response to UTP was mimicked and attenuated by ionomycin (1 uM), suggesting a dependence on Ca.sup.2+ .sub.i. Amiloride (100 uM) and hyperosmolarity (+75 mM mannitol) also decreased G .sub.t, indicating a role of cell shrinkage. Elevation of cAMP with forskolin (8 uM) or isoproterenol (10 uM) increased G .sub.t by 55 and 32%, and forskolin increased paracellular Cl.sup.- permeability by 37% without affecting mannitol permeability. The opposite effects of Ca.sup.2+ .sub.i and cAMP on G .sub.t suggest an autocrine nucleotide signaling sequence where P2Y-dependent decrease in passive, paracellular Cl.sup.- transport is succeeded by a reversion of this effect due to P1-receptor-stimulated cAMP formation by adenosine originating from a time-dependent breakdown of mucosal ATP.