Putative mediator role of endothelin-1 in asthma and other lung diseases.

1. There is an increasing amount of research to implicate endothelin (ET)-1, a member of a family of 21 amino acid peptides, as a potentially important mediator in pulmonary diseases, in particular asthma and pulmonary hypertension. Thus, ET-1 fits several of the standard criteria that need to be fulfilled for a pathophysiologically relevant substance. 2. Endothelin-1 is present in abundance in human lung: the major loci for ET-1 are the epithelium, endothelium, endocrine cells and inflammatory cells. Furthermore, the receptors that mediate the biological effects of ET-1, the ETA and ETB receptor subtypes, are found in human lung, predominantly in airway smooth muscle, and vascular smooth muscle and, to a lesser extent, nerves. There is no change in the relative proportions of ETA and ETB receptors in asthmatic versus non-asthmatic bronchial smooth muscle and peripheral lung. 3. Several studies have shown that ET-1 mimics several of the features of asthma (including bronchospasm, airway remodelling, inflammatory cell recruitment and activation, oedema, mucus secretion, airway hyperreactivity and dysfunction in neuronal inputs); however, some other reports are at odds with these findings. 4. Endothelin-1 mimics the two classical features of pulmonary hypertension (pulmonary vascular constriction and remodelling), which is often a serious complication of chronic obstructive pulmonary disease. 5. Intranasal ET-1 produces several of the symptoms of allergic rhinitis. 6. There are several reports of increased levels and/or expression of ET in patients with many pulmonary disorders, in particular asthma or pulmonary hypertension, with some evidence of a correlation between ET amounts and disease severity; however, other studies do not confirm these observations. 7. Despite these intriguing data in support of a pathophysiological role of ET-1 in lung disease, the definitive test and most difficult criteria to fulfil, the clinical evaluation of ET receptor antagonists or ET synthesis inhibitors, has still to be conducted. Only after these pivotal data are available will we be able to determine definitively whether ET-1 is a pathophysiologically important mediator in lung diseases or merely an interesting peptide with several effects in the pulmonary system.