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

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.

[1]  S. Payne,et al.  Sphingosine‐1‐phosphate and the immunosuppressant, FTY720‐phosphate, regulate detrusor muscle tone , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  A. Shiraishi,et al.  The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor. , 2007, Biochemical and biophysical research communications.

[3]  I. Darby,et al.  Fibroblast differentiation in wound healing and fibrosis. , 2007, International review of cytology.

[4]  Vineeth Rajkumar,et al.  New developments in fibroblast and myofibroblast biology: Implications for fibrosis and scleroderma , 2007, Current rheumatology reports.

[5]  T. Kanda,et al.  Extracellular mechanism through the Edg family of receptors might be responsible for sphingosine-1-phosphate-induced regulation of DNA synthesis and migration of rat aortic smooth-muscle cells. , 2001, The Biochemical journal.

[6]  H. Arai,et al.  Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species , 2000, FEBS letters.

[7]  K. Fukuzawa,et al.  Human platelets respond differentially to lysophosphatidic acids having a highly unsaturated fatty acyl group and alkyl ether-linked lysophosphatidic acids. , 2002, The Biochemical journal.

[8]  J. Walecki,et al.  Beta thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis. , 2005, Annals of the rheumatic diseases.

[9]  G. Mills,et al.  Alkoxymethylenephosphonate Analogues of (Lyso)phosphatidic Acid Stimulate Signaling Networks Coupled to the LPA2 Receptor , 2007, ChemMedChem.

[10]  G. Mills,et al.  Phosphorothioate Analogues of Alkyl Lysophosphatidic Acid as LPA3 Receptor‐Selective Agonists , 2006, ChemMedChem.

[11]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[12]  Duane D. Miller,et al.  Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry. , 2001, Analytical biochemistry.

[13]  Kazuhiro Nakamura,et al.  Both Plasma Lysophosphatidic Acid and Serum Autotaxin Levels are Increased in Chronic Hepatitis C , 2007, Journal of clinical gastroenterology.

[14]  Robert V Farese,et al.  LPA3 receptor mediates chemotaxis of immature murine dendritic cells to unsaturated lysophosphatidic acid (LPA) , 2007, Journal of leukocyte biology.

[15]  Oliver Distler,et al.  Rho-associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts. , 2008, Arthritis and rheumatism.

[16]  K. Ohsumi,et al.  Synthesis and evaluation of isoxazole derivatives as lysophosphatidic acid (LPA) antagonists. , 2007, Bioorganic & medicinal chemistry letters.

[17]  H. Shigemitsu,et al.  Cellular origins of fibroblasts: possible implications for organ fibrosis in systemic sclerosis , 2004, Current opinion in rheumatology.

[18]  Tokumura Akira,et al.  Involvement of lysophospholipase D in the production of lysophosphatidic acid in rat plasma. , 1986 .

[19]  Zhaohong Yin,et al.  Chloride channel activity in human lung fibroblasts and myofibroblasts. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[20]  A. Masi.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). , 1980, Bulletin on the rheumatic diseases.

[21]  David Abraham,et al.  Systemic sclerosis: a prototypic multisystem fibrotic disorder. , 2007, The Journal of clinical investigation.

[22]  J. Aoki.  Mechanisms of lysophosphatidic acid production. , 2004, Seminars in cell & developmental biology.

[23]  James F. Fries,et al.  Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. , 1980, Arthritis and rheumatism.

[24]  D. Baker,et al.  Multiple Mechanisms Linked to Platelet Activation Result in Lysophosphatidic Acid and Sphingosine 1-Phosphate Generation in Blood* , 2002, The Journal of Biological Chemistry.

[25]  Giulio Gabbiani,et al.  The myofibroblast: one function, multiple origins. , 2007, The American journal of pathology.

[26]  A. Postlethwaite,et al.  Platelet contributions to the pathogenesis of systemic sclerosis , 2007, Current opinion in rheumatology.

[27]  K. Csiszȧr,et al.  Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis , 2005, Arthritis research & therapy.

[28]  G. Prestwich,et al.  α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA , 2007, ChemMedChem.

[29]  V. Brinkmann.  Sphingosine 1-phosphate receptors in health and disease: mechanistic insights from gene deletion studies and reverse pharmacology. , 2007, Pharmacology & therapeutics.

[30]  J. Korn,et al.  Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts. Increased proportion of high collagen-producing cells in systemic sclerosis fibroblasts. , 1996, Arthritis and rheumatism.

[31]  D. Baker,et al.  Subtype-Selective Antagonists of Lysophosphatidic Acid Receptors Inhibit Platelet Activation Triggered by the Lipid Core of Atherosclerotic Plaques , 2003, Circulation.

[32]  A. Kuksis,et al.  Simple synthesis of diastereomerically pure phosphatidylglycerols by phospholipase D-catalyzed transphosphatidylation , 2004, Lipids.

[33]  M. Watsky.  Lysophosphatidic acid, serum, and hyposmolarity activate Cl- currents in corneal keratocytes. , 1995, The American journal of physiology.

[34]  F. Wollheim.  Classification of systemic sclerosis. Visions and reality. , 2005, Rheumatology.

[35]  K. Fukuzawa,et al.  Involvement of lysophospholipase D in the production of lysophosphatidic acid in rat plasma. , 1986, Biochimica et biophysica acta.

[36]  A. Kihara,et al.  Production and release of sphingosine 1-phosphate and the phosphorylated form of the immunomodulator FTY720. , 2008, Biochimica et biophysica acta.

[37]  R. Proia,et al.  Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 , 2004, Nature.

[38]  J. Chun,et al.  New developments in the biological functions of lysophospholipids , 2006, Cellular and Molecular Life Sciences CMLS.

[39]  L. Carbone,et al.  Receptor-mediated activation of a Cl(-) current by LPA and S1P in cultured corneal keratocytes. , 2002, Investigative ophthalmology & visual science.

[40]  K. Jakobs,et al.  Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. , 2007, Biochimica et biophysica acta.

[41]  J. Wain,et al.  The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak , 2008, Nature Medicine.

[42]  T. Ruzicka,et al.  Recruitment of topoisomerase I (Scl-70) to nucleoplasmic proteasomes in response to xenobiotics suggests a role for altered antigen processing in scleroderma. , 2005, Arthritis and rheumatism.

[43]  G. Valentini.  Classification of systemic sclerosis. , 1994, Clinics in dermatology.

[44]  S. Tanaka,et al.  Lysophosphatidic acids induce proliferation of cultured vascular smooth muscle cells from rat aorta. , 1994, The American journal of physiology.

[45]  H. Rabb,et al.  Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. , 2004, American journal of respiratory and critical care medicine.

[46]  V. Brinkmann,et al.  FTY720: targeting G-protein-coupled receptors for sphingosine 1-phosphate in transplantation and autoimmunity. , 2002, Current opinion in immunology.

[47]  J. Walecki,et al.  β Thromboglobulin and platelet factor 4 in bronchoalveolar lavage fluid of patients with systemic sclerosis , 2004 .