Effects of LTD₄ on Human Airway Smooth Muscle Cell Proliferation, Matrix Expression, and Contraction In Vitro: Differential Sensitivity to Cysteinyl Leukotriene Receptor Antagonists

Abstract

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.

Up-Regulation of Cysteinyl Leukotriene 1 Receptor by IL-13 Enables Human Lung Fibroblasts to Respond to Leukotriene C4 and Produce Eotaxin

“…Recently, Panettieri et al (40) reported that LTD 4 augments proliferation of human airway smooth muscle induced by epidermal growth factor (EGF). The precise mechanism underlying this synergy is unknown, but can be explained by convergence between LTD 4 signals via a G proteincoupled receptor and EGF signals via an EGFR tyrosine kinase.…”

Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?

“…Histamine stimulates proliferation via activation of c-fos [49], and ET-1 induced proliferation via the stimulation of extracellularregulated kinase microtubule associated protein kinase pathway [50]. More importantly, ET-1 and LTD 4 amplify the proliferative effect of growth factors such as EGF [51,52]. In vivo studies in a Brown-Norway rat model show that sulphidopeptide leukotrienes and ET-1 are both involved in allergen-induced increases in airway smooth muscle proliferation [9,53,54].…”

Platelets stimulate airway smooth muscle cell proliferation through mechanisms involving 5-lipoxygenase and reactive oxygen species

“…However, addition of the leukotrienes LTC 4 and LTB 4 to ASMC cultures did not elicit ASMC proliferation per se. In accordance, it was recently shown that cysteinyl leukotrienes alone did not induce proliferation, but acted in synergy with other factors [36][37][38]. Some studies indicate for a link between eicosanoids and ROS production [14,[22][23][24].…”