Potential pathophysiological role of endothelin-1 in asthma.
Although endothelin-1 (ET-1) was isolated originally from endothelial cells and the ETs were recognized initially for their cardiovascular actions, extensive research since the discovery of ET-1 has uncovered a spectrum of biological activities of the ETs in many systems, including the lung. Several standard criteria for a pathophysiologically relevant mediator must be fulfilled before ET-1 can be considered unequivocally to contribute to the pathogenesis of asthma. These include that: pathways for the synthesis, release and metabolism of ET-1 exist in the lung; ET receptors are located in relevant cells in the pulmonary system; ET-1 mimics several of the features of asthma; ET-1 levels are elevated in patients with asthma, with a correlation between amounts and disease severity; and drugs which inhibit the release and/or antagonize the biological effects of the ET-1 have therapeutic benefit in asthma. Several of these criteria are fulfilled by ET-1. Notwithstanding a lack of clinical data, there are several reports from preclinical studies indicating the effectiveness of ET receptor antagonists in models of asthma. Only after the results of clinical testing of selective ET receptor antagonists or ECE inhibitors in asthma are available will we know definitively whether ET-1 has fulfilled its promise as a significant player in lung pathophysiology.
Hay
D W
DW
Dept. of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Goldie
R G
RG