Abstract
BackgroundIncreased proliferation of airway smooth muscle (ASM) cells leading to hyperplasia and increased ASM mass is one of the most characteristic features of airway remodelling in asthma. A bioactive lipid, sphingosine-1-phosphate (S1P), has been suggested to affect airway remodelling by stimulation of human ASM cell proliferation.ObjectiveTo investigate the effect of S1P on signalling and regulation of gene expression in ASM cells from healthy and asthmatic individuals.MethodsAirway smooth muscle cells grown from bronchial biopsies of healthy and asthmatic individuals were exposed to S1P. Gene expression was analysed using microarray, real-time PCR and Western blotting. Receptor signalling and function were determined by mRNA knockdown and intracellular calcium mobilization experiments.ResultsS1P potently regulated the expression of more than 80 genes in human ASM cells, including several genes known to be involved in the regulation of cell proliferation and airway remodelling (HBEGF, TGFB3, TXNIP, PLAUR, SERPINE1, RGS4). S1P acting through S1P2 and S1P3 receptors activated intracellular calcium mobilization and extracellular signal-regulated and Rho-associated kinases to regulate gene expression. S1P-induced responses were not inhibited by corticosteroids and did not differ significantly between ASM cells from healthy and asthmatic individuals.ConclusionS1P induces a steroid-resistant, pro-remodelling pathway in ASM cells. Targeting S1P or its receptors could be a novel treatment strategy for inhibiting airway remodelling in asthma.
Highlights
Airway remodelling in asthma is characterised by increased airway smooth muscle mass, epithelial and goblet cell hyperplasia, angiogenesis and reticular basement membrane thickening caused by a repeated process of injury and repair [1]
Microarray analysis identified 88 genes regulated by S1P in airway smooth muscle (ASM) cells by 2 fold or more (Fig 1A, online supplement Table 1), including genes involved in cell proliferation and airway remodelling (HBEGF, TGFB3, Thioredoxin-interacting protein (TXNIP), PLAUR, SERPINE1), intracellular signalling (RGS4, RGS2, DUSP5, MAP2K3, DGKH) and regulation of transcription (NR4A1, NR4A3, EGR3, FOSB)
S1P signals through intracellular calcium, extracellular signal-regulated kinase (Erk)- and Rho-associated kinases for regulation of gene expression To investigate downstream signalling of S1P2 and S1P3 we studied the effect of S1P on calcium mobilisation in ASM cells
Summary
Airway remodelling in asthma is characterised by increased airway smooth muscle mass, epithelial and goblet cell hyperplasia, angiogenesis and reticular basement membrane thickening caused by a repeated process of injury and repair [1]. Simple compressive stress resulting from bronchoconstriction has been demonstrated to trigger a pro-fibrotic response reminiscent of remodelling in the absence of eosinophilic inflammation [4]. This mechanotransduction pathway has been linked with growth factor shedding and heparin-binding epidermal growth factor-like growth factor (HB-EGF) signalling [5]. S1P has been found to promote the growth of fibroblasts and production of extracellular matrix proteins [9, 10]. All of these processes have been associated with fibrotic lung remodelling
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