Pulmonary and vascular pharmacology of sphingosine 1-phosphate

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Dysregulation of vasomotor tone, endothelial barrier function and immune cell trafficking are central to the pathology of many lung diseases, including acute lung injury, adult respiratory distress syndrome, chronic obstructive pulmonary disease and asthma. There is increasing evidence that the serum sphingolipid sphingosine 1-phosphate and its G-protein-coupled receptors are pivotal not only in the regulation of lymphocyte migration, but also in the maintenance of vascular homeostasis and the preservation of permeability barriers that separate discrete compartments in the lung.

Introduction

Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that mediates diverse cellular responses such as proliferation, migration, cytoskeletal organisation, adherens junction assembly and morphogenesis [1••, 2, 3] (Figure 1). S1P is present at concentrations of 0.4–1.5 μM in blood and, like most small lipids in extracellular spaces, is bound by albumin and other plasma proteins [4]. This provides both a stable reservoir in extracellular fluids and efficient delivery to high-affinity cell-surface receptors (see below). A steep gradient in S1P concentration (about 25 times less) exists to the lymphatic tissue [5], and perhaps other tissues, and this is maintained by the coordinated activities of two biosynthetic sphingosine kinases (SphKs) and two biodegradative S1P phosphatases, one S1P lyase and three lysophospholipid phosphatases (Figure 1). Major producers of S1P are platelets during activation and thrombotic processes [6], mast cells during inflammatory reactions [7] and other non-haematopoietic cells such as endothelial cells (ECs) [8]. SphK1 activity and S1P production is increased by many mediators, including interleukin-1, tumour necrosis factor (TNF)-α and vascular endothelial growth factor, opening the possibility for a central role of sphingolipids in many inflammatory processes [9].

S1P binds with low nM affinity to five related G-protein-coupled receptors (GPCRs)—termed S1P1–5 (formerly Edg-1, -5, -3, -6 and -8) [1••, 10, 11]. S1P1, S1P2 and S1P3 are widely expressed and represent the dominant receptors in the cardiovascular system [12••]. S1P1 is also a dominant receptor on lymphocytes and regulates their egress from secondary lymphatic organs [13••, 14••]. S1P4 is expressed at low levels in the lymphoid system and S1P5 is expressed in the white matter tracts of the central nervous system; however, the physiological role of these receptors has not been elucidated. The cell type-specific expression of combinations of S1P receptors, together with a differential coupling to heterotrimeric G proteins and downstream signalling pathways, dramatically enhances the repertoire of any S1P stimulation. The role of S1P and its receptors in inflammation and vascular homeostasis in relation to pulmonary function is discussed below.

Section snippets

The primary step to inflammation: recruitment of specific T cells

Inflammatory infiltrates in organs and tissues comprise a collection of T cells with specificity for antigens present in the target organ. These rare’ specific cells recruit a large population of non-specific T cells and other leucocytes (macrophages, neutrophils, mast cells, eosinophils) which then initiate a cascade of inflammatory processes [15]. Using S1P1 receptor-deficient mice and T cell receptor-transgenic models it could be shown that S1P and S1P1 are pivotal in the regulation of T

Regulation of the vasomotor tone

Pulmonary vasoconstriction is believed to be an early component of the pulmonary hypertensive process. Excessive vasoconstriction has been related to endothelial dysfunction and chronically impaired production of vasodilators such as nitric oxide and prostacyclin, along with overexpression of vasoconstrictors such as endothelin-1 [27]. There is now increasing evidence that S1P and its receptors S1P1, S1P2 and S1P3 are pivotal to vascular maturation and the maintenance of vasomotor tone.

Increase of endothelial barrier function through S1P1

The vascular endothelium provides a permeability barrier between blood and the extravascular space, which, because of the large surface area of the microvascular network, is particularly sensitive [34••] (Figure 2a). Two molecular complexes, adherens junctions and tight junctions account for intercellular adhesion, although the contribution of tight junctions appears to be higher in the epithelium [35]. Several recent studies demonstrated that administration of S1P to experimental animals

Decrease of alveolar epithelial barrier function through S1P3

Inhaled air travels through the trachea into lung bronchi and bronchioles to reach the alveoli. The lumen of the alveoli is separated from the blood by the alveolar epithelium and the pulmonary capillary endothelium, termed the ‘alveolar-capillary barrier’ [44] (Figure 2b). Both type I and type II alveolar epithelium, but not capillary endothelium, express S1P3 [35]. It was recently found that S1P administration through the airways, but not through the vasculature, induced pulmonary oedema in

Mast cells, airway remodelling and asthma

Bronchial asthma is characterised by airways smooth muscle hypertrophy and infiltration of mast cells in the bronchial mucosa where they secrete various substances that initiate and perpetuate allergic responses [46]. Mast cells also lead to the production of a variety of cytokines/chemokines in epithelial cells and fibroblasts and induce the recruitment of basophils and eosinophils into sites of allergic inflammation, as well as their own intraepithelial accumulation [46]. Recent studies

Counter regulation of S1P by other sphingolipid metabolites

The biological effects of S1P are further modulated by other sphingolipid metabolites, including sphingosine, ceramide and ceramide 1-phosphate (C1P) (Figure 1). Several groups have shown that ceramide acts as a ‘pro-apoptotic’ mediator that counter regulates the ‘pro-survival’ activity of S1P [51] apparently by activating caspases and inducing clustering of death receptors in the cell membrane [52]. Like S1P, ceramide is generated from membrane sphingomyelin through the extracellular enzyme

Conclusions

There is increasing evidence that S1P and its GPCRs are pivotal in the regulation of immune cell trafficking and vascular homeostasis. S1P displays distinct effects on immune cells, endothelial and epithelial cells and SMCs, which suggests that the sphingolipid-metabolising enzymes, as well as individual S1P receptor subtypes, may provide novel therapeutics targets for the treatment of pulmonary disorders.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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