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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 3, September, 2001 316-325

Differential Adrenomedullin Release and Endothelin Receptor Expression in Distinct Subpopulations of Human Airway Smooth-Muscle Cells

Paul D. Upton, John Wharton, Neil Davie, Mohammad A. Ghatei, David M. Smith, and Nicholas W. Morrell

Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge; and Departments of Metabolic Medicine and Histochemistry, Imperial College School of Medicine, Hammersmith Campus, London, United Kingdom

Although adrenomedullin (ADM) is implicated in the control of airway tone, regulation of ADM release from airway smooth-muscle cells (ASMCs) has not been explored. Preliminary experiments have indicated that human ASMC populations were heterogeneous in their rate of ADM release and expression of endothelin (ET)A and ETB receptors. We isolated these phenotypically distinct ASMCs from explants derived from the same airway segment. ASMCs possessing exclusively ETA receptors appeared smaller and proliferated faster than ETA/ETB isolates. Macroautoradiographic analysis confirmed the presence of both receptors in human bronchi. ADM release and messenger RNA expression was greater in ETA/ETB isolates compared with ETA isolates. No measurable ET release was detected from ASMCs. Exogenous ET-1 (1 to 100 nM) more potently stimulated the release of ADM from ETA/ETB compared with ETA isolates. In addition, ET-3 (1 to 100 nM) stimulated ADM release only from ETA/ETB isolates, implicating the ETB receptor in this response. Exogenous ET-1 potentiated platelet- derived growth factor-stimulated [3H]thymidine uptake in ETA/ ETB but not ETA isolates. ET-3 did not affect [3H]thymidine uptake in either cell type. Possession of ETA/ETB receptors is associated with higher rates of ADM release and slower proliferation, but a capacity for ET-1 stimulated DNA synthesis via ETA receptors. These results support a paracrine role for the regulation of ADM release predominantly via the ETB receptor in human ASMCs.

Abbreviations: adrenomedullin, ADM; airway smooth muscle, ASM; ASM cell, ASMC; bovine serum albumin, BSA; cyclic adenosine monophosphate, cAMP; complementary DNA, cDNA; chronic obstructive pulmonary disease, COPD; ethylenediaminetetraacetic acid, EDTA; endothelin, ET; fetal bovine serum, FBS; concentration for half-maximal inhibition, IC50; immunoglobulin, Ig; Medium 199, M199; messenger RNA, mRNA; phosphate-buffered saline, PBS; platelet-derived growth factor, PDGF; radioimmunoassay, RIA; Sarafotoxin 6c, S6c; sodium dodecyl sulfate, SDS; standard error of the mean, SEM; serum-free M199, SFM.






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Copyright © 2001 American Thoracic Society. 		  Red In Translatin