Sphingosine-1-phosphate induces pro-remodelling response in airway smooth muscle cells

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.

Effect of Sphingosine 1-Phosphate on Cyclo-Oxygenase-2 Expression, Prostaglandin E2 Secretion, and β2-Adrenergic Receptor Desensitization

“…is a bioactive sphingolipid found in increased levels in the BAL of people with allergic asthma (12), with effects on asthmatic inflammation and bronchoconstriction in vitro (15,16) and in vivo (13,14,19). It is a legitimate target in asthma (25) and our current study reveals that in addition to its known pro-inflammatory and bronchoconstrictive functions, S1P can also induce β 2 -AR desensitization.…”

“…S1P has been shown to induce β 2 -AR desensitization in a guinea pig model of bronchoconstriction (17) and was recently shown to increase COX-2/PGE 2 in tracheal ASM cells in vitro (18). Moreover, Fuerst et al (19) reported that S1P potently regulated calcium mobilization and gene expression (including in ASM grown from bronchial biopsies from healthy and asthma individuals. Notably, an S1P analog (FTY720; fingolimod) was recently shown to be linked to exacerbation of asthma symptoms (20).…”

The phosphorylated form of FTY720 activates PP2A, represses inflammation and is devoid of S1P agonism in A549 lung epithelial cells

“…This is an important consideration for future development of PADs based on the sphingosine backbone into the respiratory clinic. This is because we discovered that S1P is elevated in asthma8 and this molecule has been shown to drive the development of a pro-inflammatory phenotype891011. Herein, we show that like FTY720, FTY720-P increases TNF-induced PP2A activity and represses the production of pro-inflammatory cytokines interleukin 6 (IL-6) and IL-8 and the enzyme cyclo-oxygenase 2 (COX-2).…”

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

“…To our knowledge, no other studies have looked directly at LPA and S1P effects on ATX expression. ATX mRNA expression levels were not signifi cantly changed in other cell types treated with LPA or S1P, as determined by gene arrays on cancer cells, smooth muscle cells, mouse embryonic fi broblasts, and human embryonic stem cells (49)(50)(51)(52)(53). However, some of these studies look at cells cultured in 10-20% FBS and all these studies were performed after р 6 h LPA or S1P treatment.…”