Epithelial Mechanisms in Airway Responses Induced by Hyperosmolarity

Hyperventilation during exercise causes evaporative water loss and hyperosmolarity of the airway surface liquid. Mucosal hyperosmolar challenge elicits airway transepithelial potential (Vt) changes followed by muscle relaxation mediated by epithelium- derived relaxing factor (EpDRF). In many cell types ion transport and functional responses are regulated by kinase signaling. We hypothesize that hyperosmolar challenge activates stress-sensitive protein kinases (PK)s in epithelium, and that the activity of PK(s) regulates epithelial bioelectric events and EpDRF release. Using a novel guinea-pig trachea perfusion apparatus, we examined the effects of ion transport blockers and kinase inhibitors on the relationship of Vt and relaxation responses induced by hyperosmolar D-mannitol. The results indicate that the epithelial bioelectric and muscle relaxation responses are not regulated by a common kinase signaling pathway. JNK and PKC regulate the hyperosmolarity-induced hyperpolarization. Inhibition of p38 potentiated the airway relaxation elicited by hyperosmolarity, thus p38 inhibitors have the treatment potential for exercise-induced asthma.