Semester

Spring

Date of Graduation

2007

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Jeffrey S. Fedan.

Abstract

There is airway dilation in normal people but obstruction in asthmatic patients during exercise; this has been thought to be initiated by hyperventilation causing evaporative water loss and hyperosmolarity of the airway surface liquid (ASL). In animal experiments the epithelium can detect osmolarity increases in the ASL and mediate relaxation of airway smooth muscle by releasing epithelium-derived relaxing factor (EpDRF), while in asthmatic patients this local regulatory function could be altered because of damage to epithelium. Challenged by hyperosmolarity, epithelial cells undergo shrinkage, volume-related ion transport, and release regulatory mediators, such as EpDRF. The changes in epithelial ion transport and EpDRF-mediated airway relaxation in response to hyperosmolarity have been found to be functionally linked in the guinea-pig isolated, perfused trachea. The two responses could be regulated through common stress-sensitive signaling pathways, and the epithelial shrinkage could be involved in the detecting hyperosmolar stress, leading to EpDRF release. We hypothesize that hyperosmolar challenge activates stress-sensitive protein kinases (PK)s, e.g. MAP kinases, in epithelium, and that the activity of PK(s) regulates epithelial bioelectric events and EpDRF release. The guinea-pig isolated, perfused trachea apparatus was used to investigate the effects of kinase and ion transport inhibitors on airway epithelial bioelectric and smooth muscle relaxation responses induced by hyperosmolarity. Western blots were used to examine the phosphorylation of p38 and JNK signaling proteins. Epithelial cell volume responses to hyperosmolarity were investigated. The results indicate that a physiologically-relevant increase in osmolarity elicits concentration-dependent epithelial hyperpolarization and smooth muscle relaxation, as well as epithelial shrinkage. The rapid and prolonged shrinkage is similar to the quick and long-lasting hyperpolarization and relaxation responses, suggesting a possible link between the epithelial shrinkage and EpDRF release. However, a common signaling pathway regulating both of the bioelectric and relaxation responses was not identified. Therefore, in terms of kinase signaling, there may not be a cause-effect relationship between the two responses. Inhibition of p38 potentiated the airway relaxation elicited by hyperosmolarity, suggesting that p38 inhibitors have the potential for the treatment of bronchoconstriction induced by exercise through the potentiation of EpDRF release.

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