EPITHELIUM-DEPENDENT RELAXATION OF AIRWAY SMOOTH MUSCLE IS LINKED TO EPITHELIAL CHLORIDE CURRENTS
This project investigated interactions between the airway epithelium and the underlying smooth muscle. The airway epithelium is the first surface exposed to inhaled compounds and may play a major role in determining the airway response to various stimuli. One component of this project entailed developing several new methods to investigate mouse tracheal physiology. The goal in developing these methods was to allow side-specific delivery of compounds to either the airway lumen or smooth muscle while simultaneously monitoring airway constriction as well as transepithelial ion movement. These new methods were applied to test several hypotheses. The first was that mouse airway epithelium modulates smooth muscle contraction by releasing epithelium-derived relaxing factors. The specific responses to substance P (SP) and ATP were evaluated, as these stimuli may be important in disease states or normal airway physiology. Both SP and ATP stimulate epithelium-dependent relaxation, and both responses are sensitive to inhibition by indomethacin, suggesting that an eicosanoid relaxing factor may be released in response to SP or ATP. Prostaglandin E 2 (PGE 2 ) is a likely mediator of these responses, and the hypothesis that PGE 2 is an important mediator of relaxation to SP or ATP was tested using mice homozygous for a gene-targeted deletion of the EP 2 receptor (EP 2 -/- ). Relaxation in response to SP or ATP was significantly reduced in tracheas from EP 2 -/- mice, and this defect was similar to the impaired relaxation to exogenous PGE 2 , thus supporting PGE 2 as a mediator in these responses. SP and ATP also stimulate chloride secretion across airway epithelium. The next hypothesis tested was that epithelium-dependent relaxation of mouse trachea depends on activation of epithelial chloride currents. Measurements of transepithelial voltage (V T ) and airway resistance showed that chloride currents preceded and were linked to relaxation. Blocking chloride currents inhibited V T changes and relaxation to SP or ATP; enhancing chloride secretion increased the responses. The signaling pathway linking chloride secretion to mediator release involves calcium release from intracellular stores. These new findings may lead to important new insights regarding airway diseases such as cystic fibrosis where impaired epithelial chloride currents may affect the release of epithelium-derived factors.
School:University of Cincinnati
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:substance p adenosive triphosphate prostaglandins mouse
Date of Publication:01/01/2001