EFFECTS OF LTD4 ON HUMAN AIRWAY SMOOTH-MUSCLE CELL-PROLIFERATION, MATRIX EXPRESSION, AND CONTRACTION IN-VITRO - DIFFERENTIAL SENSITIVITY TOCYSTEINYL LEUKOTRIENE RECEPTOR ANTAGONISTS

The cysteinyl leukotrienes (CysLTs) mimic many of the features of asth ma and are implicated in its pathophysiology. Little, however, is know n about the effects of the CysLTs on airways remodeling. In this study the effects of leukotriene D-4 (LTD4) on human airway smooth muscle ( HASM) cell proliferation and expression of extracellular matrix protei ns were investigated. LTD4 (0.1-10 mu M) alone had no effect on DNA sy nthesis in HASM. LTD4, however, markedly augmented proliferation induc ed by the mitogen, epidermal growth factor (EGF, 1 ng/ml). The potenti ating effect of LTD4 (1 mu M) On EGF-induced DNA synthesis was abolish ed by pranlukast (1 mu M) or pobilukast (30 mu M), but unaffected by z afirlukast (1 mu M). In contrast, pranlukast (pK(B) = 6.9), pobilukast (pK(B) = 7.0), and zafirlukast (pK(B) = 6.5) had equivalent potencies for inhibition of LTD4-induced contraction in human bronchus. LTD4 (0 .1 or 10 mu M) did not increase the total messenger RNA expression of the extracellular matrix proteins (pro-alpha[I] type I or alpha 1[IV] type IV collagen), elastin, biglycan, decorin, and fibronectin, and di d not influence tumor growth factor-beta (10 ng/ml)-induced effects on the expression of these proteins in HASM cells. These data indicate t hat LTD4 augments growth factor-induced HASM proliferation but does no t 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 fro m that which mediates LTD4-induced HASM contraction. Collectively, the se results provide preliminary evidence that CysLTs may play a role in airways remodeling in asthma.