Jing Y, Dowdy JA, Van Scott MR, Fedan JS
Hyperosmolarity-induced dilation and epithelial bioelectric responses of guinea-pig trachea in vitro. Role of kinase signaling. [JOURNAL ARTICLE]
J Pharmacol Exp Ther 2008 Apr 15.
Exercise-induced airway obstruction is thought to involve evaporative water loss and hyperosmolarity of the airway surface liquid. Hyperosmolar challenge of the epithelium of isolated, perfused guinea-pig trachea rapidly alters transepithelial potential difference (Vt) and elicits smooth muscle relaxation mediated by epithelium-derived relaxing factor (EpDRF). In many cell types protein kinases mediate responses to hyperosmolarity and regulatory volume increase. In this study, inhibitors were used to investigate the involvement of kinases and phosphatases in bioelectric responses of epithelium to hyperosmolarity and their possible relationship to EpDRF-mediated relaxation. After contraction of the perfused trachea with extraluminal methacholine, D-mannitol applied intraluminally (</=80 mosM) increased Vt and elicited dilation of the smooth muscle with a similar concentration-dependence; higher concentrations decreased Vt. In tracheas exposed to 30 mosM D-mannitol (~EC50), SB 203580 and SKF 86002 (p38 inhibitors) potentiated the dilation, while SP 600125 and dicumarol (JNK inhibitors), chelerythrine (non-selective PKC inhibitor) and NaAsO2 (MAPK stress inducer) and Na3VO4 (protein tyrosine phosphatase inhibitor), inhibited hyperpolarization. Large increases in the phosphorylation of p38 and JNK occurred at concentrations higher than those needed to elicit functional responses. The PI-3-K inhibitor, LY 294002, and Na3VO4 did not affect the Vt responses, but inhibited methacholine-induced constriction; SP 600125 and dicumarol potentiated, and chelerythrine inhibited, methacholine-induced epithelial hyperpolarization. These results suggest that JNK, PKC and phosphatase(s) are involved in hyperosmolarity-induced hyperpolarization of the tracheal epithelium, but that p38 is involved in EpDRF-mediated relaxation.
More from this journal |
