Effects of LTD4 on human airway smooth muscle cell proliferation, matrix expression, and contraction In vitro: differential sensitivity to cysteinyl leukotriene receptor antagonists.
The cysteinyl leukotrienes (CysLTs) mimic many of the features of asthma and are implicated in its pathophysiology. Little, however, is known about the effects of the CysLTs on airways remodeling. In this study the effects of leukotriene D4 (LTD4) on human airway smooth muscle (HASM) cell proliferation and expression of extracellular matrix proteins were investigated. LTD4 (0.1-10 microM) alone had no effect on DNA synthesis in HASM. LTD4, however, markedly augmented proliferation induced by the mitogen, epidermal growth factor (EGF, 1 ng/ml). The potentiating effect of LTD4 (1 microM) on EGF-induced DNA synthesis was abolished by pranlukast (1 microM) or pobilukast (30 microM), but unaffected by zafirlukast (1 microM). In contrast, pranlukast (pKB = 6.9), pobilukast (pKB = 7.0), and zafirlukast (pKB = 6.5) had equivalent potencies for inhibition of LTD4-induced contraction in human bronchus. LTD4 (0.1 or 10 microM) did not increase the total messenger RNA expression of the extracellular matrix proteins (pro-alpha[I] type I or alpha1[IV] type IV collagen), elastin, biglycan, decorin, and fibronectin, and did not influence tumor growth factor-beta (10 ng/ml)-induced effects on the expression of these proteins in HASM cells. These data indicate that LTD4 augments growth factor-induced HASM proliferation but does not alter the expression of various extracellular matrix components. The observed differences in sensitivity to the antagonists suggests that the former phenomenon may be mediated by a CysLT receptor distinct from that which mediates LTD4-induced HASM contraction. Collectively, these results provide preliminary evidence that CysLTs may play a role in airways remodeling in asthma.
Panettieri
R A
RA
Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, USA.
Tan
E M
EM
Ciocca
V
V
Luttmann
M A
MA
Leonard
T B
TB
Hay
D W
DW
D001249:Asthma / Q000503:physiopathology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D003998:Dicarboxylic Acids / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007211:Indoles; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000494:pharmacology*; D008565:Membrane Proteins; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D048448:Phenylcarbamates; D012333:RNA, Messenger / Q000187:drug effects; D018077:Receptors, Leukotriene; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D002867:Chromones; D003998:Dicarboxylic Acids; D016326:Extracellular Matrix Proteins; D007211:Indoles; D020024:Leukotriene Antagonists; D008565:Membrane Proteins; D048448:Phenylcarbamates; D012333:RNA, Messenger; D018077:Receptors, Leukotriene; D013449:Sulfonamides; D014105:Tosyl Compounds; D016212:Transforming Growth Factor beta; D004815:Epidermal Growth Factor; D017998:Leukotriene D4; D002217:Carbachol; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor; C052393:pobilukast; C047681:pranlukast; C062735:zafirlukast