Published ahead of print on September 3, 2004, doi:10.1165/rcmb.2003-0331OC
© 2004 American Thoracic Society DOI: 10.1165/rcmb.2003-0331OC Endothelin-1 Inhibits Mucin Secretion from Ovine Airway Epithelial Goblet CellsSchool of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton; Pfizer Global Research and Development, Sandwich, Kent; Respiratory Cell and Molecular Biology Division, University of Southampton, Southampton, United Kingdom; Department of Anatomy II: Experimental Morphology, University of Hamburg, Hamburg, Germany Address correspondence to: Dr. Michael I. Lethem, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton BN2 4GJ, UK. E-mail: m.i.lethem{at}brighton.ac.uk Mucus hypersecretion is a feature of several respiratory diseases and frequently leads to obstruction of small airways where the principal source of mucous glycoproteins (mucins), the major macromolecular constituents of mucus, are goblet cells. Hence, inhibition of mucin secretion from these cells may be clinically beneficial. In this study, we have developed a lectin-based assay for mucin secretion from ovine airway goblet cells and used this assay to investigate the regulation of these cells by endothelin (ET)-1. ET-1 inhibited baseline mucin secretion (maximum inhibition: 60.3 ± 4.2%, 50% inhibitory concentration: 0.8 ± 0.17 nM). This response was abolished by the ETA antagonist, BQ-123 (1 µM), but not by the ETB antagonist, BQ-788 (1 µM). ET-1 (1 µM) did not affect mucin secretion stimulated by ATP (100 µM) but secretion in response to ATP (10 µM) was inhibited by 63.3 ± 11.8%. This response could be eliminated by BQ-123, but not by BQ-788. Radioligand binding and immunohistochemistry indicated the expression of both ETA- and ETB-receptors on the epithelium. In summary, ET-1, acting via ETA-receptors, inhibits baseline and ATP-stimulated mucin secretion from ovine airway goblet cells. This represents the first report of a physiologic mechanism for inhibiting airway goblet cell mucin secretion; an understanding of this mechanism may provide opportunities for the treatment of obstructive airways disease.
Abbreviations: maximum binding, Bmax • calcium, Ca2+ • Chinese hamster ovary, CHO • distilled water, dH2O • enzyme-linked lectin-binding assay, ELLA • endothelin, ET • Helix pomatia agglutinin, HPA • dissociation constant, KD • minimal essential medium, MEM • mucous glycoprotein, mucin • phosphate-buffered saline, PBS • phospholipase C, PLC • sarafatoxin S6b, SRTX6b • sarafatoxin S6c, SRTX6c This article has been cited by other articles:
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