Semester

Fall

Date of Graduation

2000

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Physiology, Pharmacology & Neuroscience

Committee Chair

Jeffrey S. Fedan.

Abstract

In response to elevated serosal or mucosal tonicity, guinea-pig tracheal epithelium releases the non-nitric oxide, non-prostanoid, epithelium-derived relaxing factor (EpDRF), which subsequently diffuses to the underlying airway smooth muscle to initiate relaxation. Hypertonicity-induced smooth muscle relaxation via EpDRF involves epithelial Na+ and Cl- channels and is preceded by a depolarization of the transepithelial potential difference (Vms). By utilizing two different experimental systems, this study sought to characterize further the airway epithelial bioelectric mechanisms associated with the effects of EpDRF in guinea-pig isolated trachea.;First, this study attempted to elucidate which epithelial ion channels and/or transporters are involved in the depolarization of the Vms. This was accomplished by determining the effect of ion channel and transporter inhibitors on in vitro transepithelial short-circuit current responses to elevated mucosal tonicity in guinea-pig tracheal segments mounted in Ussing chambers. The data from these studies indicate that apical Na + channels and the basolateral Na+-K+-2Cl - cotransporter are intimately involved in the epithelial bioelectric response to elevated mucosal tonicity, and thus, may play an important role in the synthesis, release, and/or effects of EpDRF.;Secondly, this study sought to determine the consequences of altered epithelial ion transport, following LPS-treatment (4 mg/kg, i.p.; 18 hr post-treatment), on EpDRF-induced smooth muscle relaxation and its associated bioelectric events as well as airway reactivity to methacholine (MCh). In vitro tracheal smooth muscle contractile and relaxant responses as well as V ms responses were measured utilizing the isolated and modified isolated, perfused trachea apparatuses while the two-chambered, whole-body plethysmograph was used to measure in vivo airway reactivity. This study has shown that EpDRF-induced smooth muscle relaxation and its associated bioelectric events are either increased, decreased, or not changed following LPS-induced alterations of epithelial ion transport. In addition, LPS-treatment causes in vivo airway hyporeactivity to MCh. These results suggest that the effects of EpDRF on smooth muscle reactivity are modulated by changes in the electrical activity of the epithelium which can ultimately impact on airway reactivity to MCh.

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