The endothelins in the pulmonary system

Although initial research interest in the ETs was focused on their cardiovascular effects, it is now clearly established that these peptides have wide-ranging activities in the respiratory tract. Importantly, ET-1 is synthesized, stored, released and metabolized in the lung, suggesting that these activities may be relevant to both physiological function and to pathophysiological processes in the lung. To the present time, only two ET receptor subtypes have been definitively characterized in the lung, namely ET(A) and ET(B) receptors, both of which have been shown to mediate contraction and mitogenesis in airway smooth muscle from humans and animals. However, the possibility that further receptor subtypes might be defined from functional, biochemical and molecular biological studies cannot be dismissed. It is apparent that the ETs may have a role to play in the pathogenesis of several pulmonary diseases. However, most of the current evidence for this falls short of establishing convincing causal associations. Perhaps the most convincing data relate to pulmonary hypertension. Although it is too early to ascribe a role for the ETs in the pathophysiology of asthma, the preliminary data are intriguing. Thus far, research has centred largely on the bronchoconstrictor effects of ET-1 in vitro and in vivo. In relation to asthma, it is important that future studies should focus increasingly on the effects of the ETs in nerves and inflammatory cells. In addition, the effects of chronic airway exposure to ET-1 on smooth muscle and fibroblast proliferation is an important area for future research. The unequivocal testing of the pathophysiological role of the ETs in asthma requires the clinical evaluation of potent and selective receptor antagonists for the various ET receptor subtypes. It seems likely that these studies will be conducted in the not-too-distant future, as compounds which possess the appropriate pharmacological profile become available for clinical evaluation. Additionally, ECE-1 and ECE-2 present as potentially important targets for therapeutic intervention, although the development of selective nonpeptide inhibitors may be some years away.