Endothelin-1 inhibits mucin secretion from ovine airway epithelial goblet cells

TY - JOUR

T1 - Endothelin-1 inhibits mucin secretion from ovine airway epithelial goblet cells

AU - Clancy, Sinead M

AU - Yeadon, Michael

AU - Parry, John

AU - Yeoman, Mark S

AU - Adam, Elizabeth C

AU - Schumacher, Udo

AU - Lethem, Michael I

PY - 2004/12

Y1 - 2004/12

N2 - 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 ET(A) antagonist, BQ-123 (1 muM), but not by the ET(B) antagonist, BQ-788 (1 muM). ET-1 (1 muM) did not affect mucin secretion stimulated by ATP (100 muM) but secretion in response to ATP (10 muM) 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 ET(A)- and ET(B)-receptors on the epithelium. In summary, ET-1, acting via ET(A)-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.

AB - 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 ET(A) antagonist, BQ-123 (1 muM), but not by the ET(B) antagonist, BQ-788 (1 muM). ET-1 (1 muM) did not affect mucin secretion stimulated by ATP (100 muM) but secretion in response to ATP (10 muM) 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 ET(A)- and ET(B)-receptors on the epithelium. In summary, ET-1, acting via ET(A)-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.

KW - Animals

KW - Endothelin-1

KW - Epithelial Cells

KW - Goblet Cells

KW - Immunohistochemistry

KW - Lectins

KW - Mucins

KW - Protein Binding

KW - Radioligand Assay

KW - Receptors, Endothelin

KW - Sheep

KW - Trachea

U2 - 10.1165/rcmb.2003-0331OC

DO - 10.1165/rcmb.2003-0331OC

M3 - SCORING: Journal article

C2 - 15347558

VL - 31

SP - 663

EP - 671

JO - AM J RESP CELL MOL

JF - AM J RESP CELL MOL

SN - 1044-1549

IS - 6

ER -