The influence of epithelium on the responsiveness of guinea‐pig isolated trachea

Abstract

This study was designed to investigate the possibility that tracheal epithelium generates a relaxant factor analogous to the endothelial‐derived relaxant factor (EDRF) of vascular tissue. The absence of such a factor following epithelial damage in diseases such as asthma might help to explain the airway hyperreactivity characteristic of such diseases. Removal of epithelium by rubbing enhanced the sensitivity of guinea‐pig isolated tracheal chains to 5‐hydroxytryptamine, histamine, acetylcholine, adenosine, isoprenaline and also minimally to KC1. Responses to LaCl3 and electrical field stimulation were not affected. Low concentrations of adenosine produced contractions only in tissues denuded of epithelium. In the presence of indomethacin 1.4 μM or dithiothreitol (DTT) 1 μM, dose‐response curves to histamine were moved to the left in both control and rubbed tissues, and the maximum response was increased. The difference in sensitivity between tissues with and without epithelium was not affected by indomethacin, but was slightly reduced by DTT. Phenidone (0.1 mM) also increased the maximum responses, but increased the sensitivity only of the tissues with intact epithelium, to the same level as that seen in the tissues denuded of epithelium. Superfusion cascade studies provided no evidence for the generation of a relaxant factor from tracheal epithelium. It is suggested that the supersensitivity produced by removal of the epithelium is not due to the removal of a relaxant factor, but rather to the removal of a permeability barrier, allowing a greater concentration of agonist at the level of the underlying smooth muscle.

The epithelium and the pharmacology of guinea‐pig tracheal tone in vitro

“…Effects of epithelium removal, if any, on other contractile actions also vary. Contractions produced by one or more of histamine, muscarinic agents, 5-hydroxytryptamine, and K' were slightly increased (either pD2 or E,,, or both) (Flavahan et al, 1985;Barnes et al, 1985;Hay et al, 1986a,b;Raeburn et al, 1986ab;Finnen et al, 1986;Holroyde, 1986), or reduced (this study, cf. Whalley, 1978), or were not affected by epithelium removal (Goldie et al, 1986;Raeburn et al, 1986a, Hay et al, 1986aThompson et al, 1986 and this study).…”

“…Barnes et al (1985) found that indomethacin did not alter a slightly increased sensitivity to acetylcholine in bovine epithelium-denuded tracheae. In guinea-pig trachea Holroyde (1986) found that indomethacin moved histamine dose-response curves to the left in both control and epitheliumdenuded preparations. Hay et al (1986b), also working with guinea-pig trachea, demonstrated that indomethacin was without effect on the sensitivity to histamine but produced the same effect as epithelium removal on the EC50 value of methacholine (that was significantly reduced by a factor of about 2).…”

“…The initial work by Flavahan et al (1985) in dog bronchi suggested that the response to electrical field stimulation, in particular the duration of the contraction, was increased by epithelium removal. However, later work by Barnes et al (1985) in bovine trachea, Holroyde (1986) and Thompson et al (1986) in cat and guinea-pig trachea, demonstrated no effect of epithelium on the response to electrical field stimulation. Effects of epithelium removal, if any, on other contractile actions also vary.…”

“…Holroyde (1986) reported contractions to adenosine only in epithelium-denuded tracheal preparations. However, in this study biphasic responses to adenosine in both types of preparation were recorded.…”

“…It has had an impact on work with isolated airway preparations where the focus has been on a role for the epithelium in regulation of airway smooth muscle tone. Despite the fact that many of the accumulated observations are negative or contradictory, it has generally been maintained that airway epithelium importantly affects tracheobronchial smooth muscle reactivity (Barnes et al, 1985;Flavahan et al, 1985;Farmer et al, 1986;Finnen et al, 1986;Frossard & Muller, 1986;Goldie et al, 1986;Hay et al, 1986a,b;Holroyde, 1986;Reaburn et al, 1986a,b;Thompson et al, 1986;Tschirhart & Landry, 1986;Nijkamp & Folkerts, 1987). It is understandable that positive results have been searched for and related to the pathology and pharmacology of asthma.…”