Sphingosine 1‐phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma

Abstract

Asthma is characterized by airway inflammation, remodeling, and hyperresponsiveness to contractile stimuli that promote airway constriction and wheezing. Here we present evidence that sphingosine 1-phosphate (SPP) is a potentially important inflammatory mediator implicated in the pathogenesis of airway inflammation and asthma. SPP levels were elevated in the airways of asthmatic (but not control) subjects following segmental antigen challenge, and this increase was correlated with a concomitant increase in airway inflammation. Because human airway smooth muscle (ASM) cells expressed EDG receptors for SPP , we examined whether SPP may play a role in airway inflammation and remodeling, by affecting ASM cell growth, contraction, and cytokine secretion. SPP is mitogenic and augments EGF-and thrombininduced DNA proliferation by increasing G 1 /S progression. SPP increased phosphoinositide turnover and intracellular calcium mobilization, the acute signaling events that affect ASM contraction. By modulating adenylate cyclase activity and cAMP accumulation, SPP had potent effects on cytokine secretion. Although SPP inhibited TNF-α-induced RANTES release, it induced substantial IL-6 secretion alone and augmented production of IL-6 induced by TNF-α. These studies are the first to associate SPP with airway inflammation and to identify SPP as an effective regulator of ASM growth, contraction and synthetic functions.Key words: cAMP • EDG receptors • cytokines • mitogenesis • cytosolic calcium sthma, a common chronic disease, is characterized by airway hyper-responsiveness and reversible airflow obstruction. Exposure to environmental antigen, a frequent trigger of acute asthmatic attacks, induces an inflammatory reaction in the airway characterized in part by an influx of lymphocytes and eosinophils that secrete various agents capable of A perpetuating inflammation and provoking airway smooth muscle (ASM) contraction. Accordingly, the majority of therapeutic agents in asthma seek to minimize the development or consequences of airway inflammation or directly promote ASM relaxation.Recently, a more chronic feature of asthma, termed "airway remodeling", has drawn the attention of asthma research. Airway remodeling refers to structural alterations in the bronchial wall characterized by ASM hypertrophy and hyperplasia, epithelial denudation, mucus gland hyperplasia, lamina recticularis thickening, and vasculogenesis. The functional consequence of these histological findings is to render the airway irreversibly obstructed in some susceptible asthmatics. Others (1-4) and we (5) have recently suggested a prominent role for ASM in orchestrating both the acute inflammatory reaction and the chronic features of airway remodeling that occur in asthma. This assertion is supported by observations that ASM mass is increased in the bronchi of severe chronic asthmatics (6), that numerous agents that are elevated in the asthmatic airway are mitogenic to ASM in vitro (5), and that ASM expresses adhesion molecules (7) and secretes numerous cytokin...

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