Role of endothelin-1 in regulating proliferation of cultured rabbit airway smooth muscle cells.
Increased expression of the potent vasoconstrictor and bronchoactive peptide, endothelin-1 (ET-1), has recently been demonstrated in airway epithelial and endothelial cells of asthmatic patients. To identify its potential role in contributing to airway smooth muscle (ASM) hyperplasia, a characteristic feature of asthmatic airways, the mitogenic action of ET-1 was investigated in cultured rabbit ASM cells. ET-1 elicited significant dose-dependent (10(-12)-10(-6) M) increases in ASM cell number, with a mean potency (i.e., -log mean effective dose) of action of 9.82-log M. ET-1 also acutely stimulated intracellular inositol 1,4,5-trisphosphate accumulation. The latter response was blocked by phospholipase C inhibition with neomycin; however, neomycin had no effect on the promitogenic action of ET-1. By contrast, the ASM cell proliferative response to ET-1 was independently inhibited by pertussis toxin, inhibitors of phospholipase A2, cyclooxygenase, and thromboxane A2 (TxA2) synthesis, as well as blockade of the TxA2 receptor. Moreover, in complementary studies, we found that administration of the stable TxA2 mimetics, carbocyclic TxA2 (CTA2) and U-46619, induced ASM cell proliferation and that ET-1 evoked the release of endogenous TxA2 from the ASM cells. Collectively, these observations provide new evidence that 1) ET-1 is a potent mitogen of ASM cells, 2) the promitogenic effect of ET-1 is associated with activation of a pertussis toxin-sensitive G protein coupled to stimulation of phospholipase A2, and 3) the latter mediates ASM cell proliferation via the release and autocrine mitogenic action of TxA2. The findings support a potential role for ET-1 in mediating the characteristic hyperplasia of ASM in asthma.
Noveral
J P
JP
Division of Pulmonary Medicine, Joseph Stokes, Jr., Research Institute, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia 19104.
Rosenberg
S M
SM
Anbar
R A
RA
Pawlowski
N A
NA
Grunstein
M M
MM
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016232:Endothelins / Q000502:physiology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009130:Muscle, Smooth / Q000166:cytology*; D010741:Phospholipases A / Q000502:physiology; D054467:Phospholipases A2; D011817:Rabbits; D015398:Signal Transduction; D013931:Thromboxanes / Q000502:physiology; D014132:Trachea / Q000166:cytology*; D010738:Type C Phospholipases / Q000502:physiology
D016232:Endothelins; D013931:Thromboxanes; D015544:Inositol 1,4,5-Trisphosphate; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases