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      Elevated Serum Levels of Arachidonoyl-lysophosphatidic Acid and Sphingosine 1-Phosphate in Systemic Sclerosis

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          Systemic sclerosis (SSc) is an often fatal disease characterized by autoimmunity and inflammation, leading to widespread vasculopathy and fibrosis. Lysophosphatidic acid (LPA), a bioactive phospholipid in serum, is generated from lysophospholipids secreted from activated platelets in part by the action of lysophospholipase D (lysoPLD). Sphingosine 1-phosphate (S1P), a member of the bioactive lysophospholipid family, is also released from activated platelets. Because activated platelets are a hallmark of SSc, we wanted to determine whether subjects with SSc have altered serum lysophospholipid levels or lysoPLD activity. Lysophospholipid levels were measured using mass spectrometric analysis. LysoPLD activity was determined by quantifying choline released from exogenous lysophosphatidylcholine (LPC). The major results were that serum levels of arachidonoyl (20:4)-LPA and S1P were significantly higher in SSc subjects versus controls. Furthermore, serum LPA:LPC ratios of two different polyunsaturated phospholipid molecular species, and also the ratio of all species combined, were significantly higher in SSc subjects versus controls. No significant differences were found between other lysophospholipid levels or lysoPLD activities. Elevated 20:4 LPA, S1P levels and polyunsaturated LPA:LPC ratios may be markers for and/or play a significant role in the etiology of SSc and may be future pharmacological targets for SSc treatment.

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          Most cited references 43

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          A rapid method of total lipid extraction and purification.

           E G BLIGH,  W. Dyer (1959)
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            Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.

            Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
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              The myofibroblast: one function, multiple origins.

              The crucial role played by the myofibroblast in wound healing and pathological organ remodeling is well established; the general mechanisms of extracellular matrix synthesis and of tension production by this cell have been amply clarified. This review discusses the pattern of myofibroblast accumulation and fibrosis evolution during lung and liver fibrosis as well as during atheromatous plaque formation. Special attention is paid to the specific features characterizing each of these processes, including the spectrum of different myofibroblast precursors and the distinct pathways involved in the formation of differentiated myofibroblasts in each lesion. Thus, whereas in lung fibrosis it seems that most myofibroblasts derive from resident fibroblasts, hepatic stellate cells are the main contributor for liver fibrosis and media smooth muscle cells are the main contributor for the atheromatous plaque. A better knowledge of the molecular mechanisms conducive to the appearance of differentiated myofibroblasts in each pathological situation will be useful for the understanding of fibrosis development in different organs and for the planning of strategies aiming at their prevention and therapy.

                Author and article information

                Int J Med Sci
                International Journal of Medical Sciences
                Ivyspring International Publisher (Sydney )
                5 June 2009
                : 6
                : 4
                : 168-176
                1. Department of Health Chemistry, Institute of Health Bioscience, The University of Tokushima Graduate School, 1-78-1 Shomachi, Tokushima 770-8505, Japan;
                2. Veterans Affairs Medical Center, Memphis, Tennessee, USA;
                3. Division of Rheumatology, Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA;
                4. Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, Tennessee, USA
                Author notes
                ✉ Correspondence to: Mitchell Watsky, Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Memphis, Tennessee, 38002 USA. Phone: 1-901-448-8206; Fax: 1-901-448-7126; E-mail: mwatsky@

                Conflict of Interest: The authors have declared that no conflict of interest exists.

                © Ivyspring International Publisher. This is an open-access article distributed under the terms of the Creative Commons License ( Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited.
                Research Paper


                lpc, s1p, lysophospholipids, lysophospholipase d, fibrosis, scleroderma, lpa


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