Am. J. Respir. Crit. Care Med., Vol 155, No. 6, Jun 1997, 1884-1889.
Modulation of endothelin production and metabolism in guinea-pig tracheal epithelial cells by peptidase inhibitors
Q Yang, B Battistini, P D'Orleans-Juste, AY Jeng and P Sirois
Department of Pharmacology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Endothelins (ET-1, ET-2, ET-3) are potent bronchoconstrictors and
growth-promoting mediators. They are released from various cells such as
endothelial and epithelial cells. In the airways, ETs are released under
basal and stimulated conditions. In patients with status asthmaticus and
other pulmonary disorders, the expression and production of ET-1 are
increased. We investigated the activities of endothelin-converting enzymes
(ECE) and endothelin-degrading enzymes, mostly neutral endopeptidases
(NEP), in guinea-pig tracheal epithelial cells in culture through the use
of various enzyme inhibitors. We found that among ETs, only ET-1 was
steadily released under basal conditions over 24 h. The basal production
was attenuated by both phosphoramidon and CGS 26 303, dual NEP and ECE
inhibitors. Conversely, thiorphan, a selective NEP inhibitor, did not
attenuate but rather increased the concentration of ET-1 in cell
supernatants. CGS 24 592 and SQ 28 603, other NEP inhibitors, also
increased the concentrations of ET-1 in cell supernatants in a
concentration-dependent manner. However, at a high concentration, SQ 28 603
also inhibited the basal release of ET-1, which would suggest a
non-selective inhibitory activity against ECE. These data suggest that ET-1
is simultaneously produced and degraded by guinea-pig tracheal epithelial
cells via phosphoramidon-sensitive ECE and NEP pathways, respectively. This
observation is of interest when considering that asthmatic patients were
shown to have a damaged airway epithelium combined with the loss of NEP
activity, which was associated with an increased expression and production
of ET-1.
