Epithelium-derived relaxing factor(s) and bronchial reactivity

Abstract

In isolated blood vessels, the mechanical or enzymatic removal of the endothelium augments the contractions evoked by a variety of vasoconstrictor agents, because the endothelial cells release a powerful relaxing substance(s) (endothelium-derived relaxing factor(s). The focal absence of epithelial cells in airways of patients with asthma is well documented. When the luminal surface of canine bronchi is rubbed gently, the only morphologic change observed is the disappearance of the epithelial cell layer. The removal of the epithelium causes an increased sensitivity of the bronchial smooth muscle to acetylcholine without alteration in the maximal responsiveness to the cholinergic transmitter. The augmentation cannot be attributed to reduced enzymatic breakdown of acetylcholine after removal of the epithelial cells, since it is not affected by inhibitors of acetylcholinesterase. It cannot be attributed to disappearance of a diffusion barrier, since epithelium removal also augments the contractions evoked by electrical stimulation of the cholinergic nerve endings. Removal of the epithelium potentiates the contractions evoked by histamine and 5-hydroxytryptamine in a manner similar to that observed for acetylcholine. The potentiating effect of epithelium removal is more pronounced in larger rather than in smaller bronchi. By contrast, the relaxations evoked by β-adrenergic agonists are less pronounced in bronchi without, rather than in bronchi with, epithelium. The influence of the epithelium on isoproterenol-induced relaxation is more pronounced in smaller rather than in larger bronchi. These observations suggest that the bronchial epithelium release an inhibitory factor that partially counteracts activation of the airway smooth muscle by bronchoconstrictor substances. Preliminary bioassay studies confirm that the bronchial epithelium can release a potent relaxing substance that inhibits not only bronchial but also vascular smooth muscle. In larger bronchi, the epithelium-derived relaxing factor is released under basal conditions; in smaller bronchi, its release can be activated by cathecholamines. The augmentation of the response to bronchoconstrictor agents by removal of the epithelium has been observed, in the author's and other laboratories, in isolated airways from different species.