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• W2118730462 abstract "EDITORIAL FOCUSLysophosphatidylcholine: an enigmatic lysolipidDolly MehtaDolly MehtaPublished Online:01 Aug 2005https://doi.org/10.1152/ajplung.00165.2005MoreSectionsPDF (41 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations increased endothelial permeability of pulmonary microvessels is the major contributor of acute lung injury, sepsis, and acute respiratory distress syndrome (2, 7). Studies have established that change in cell shape resulting in concurrent formation of gaps between endothelial cells is a primary determinant of increase in endothelial permeability (2, 7). Proinflammatory mediators (such as thrombin, histamine, and bradykinin) and other blood-borne mediators (such as VEGF) bind endothelial cell surface receptors and activate signaling cues that induce endothelial cell contraction, forming gaps in the monolayer (2, 7). Stress fibers composed of bundles of polymerized actin and myosin filaments are the primary elements of the contractile machinery in endothelial cells (2). These fibers were shown to form in cultured endothelial cells in response to many permeability-increasing mediators. RhoA, a monomeric GTPase, upon activation is known to form stress fibers and thus plays a central role in causing the increase in endothelial permeability (2). Studies in various cell types indicate that G protein-coupled receptor agonists, such as thrombin, activate RhoA by activating Gαq and Gα12/13 (5, 9, 14). Gq-induced activation of RhoA in endothelial cells evidently requires PKCα-dependent phosphorylation of guanosine dissociation inhibitor and p115-Rho exchange factor (3, 11).The report from Huang et al., the current article in focus (Ref. 4, see p. L176 in this issue), shows that extracellular application of lysophosphatidylcholine (LPC), which exceeded the binding capacity of albumin, activated RhoA in a PKCα-sensitive manner and impaired endothelial barrier function. LPC (2 μM) given alone also perturbed endothelial barrier function, indicating functional effects of LPC in vivo may be controlled by a balance between free form and albumin-bound form of LPC. Although endothelium was shown to be a target for LPC in several studies, it was not known whether LPC per se regulates endothelial barrier integrity. For example, LPC was shown to impair endothelial cell function by preventing the synthesis of endothelium-derived relaxing factor (12). LPC also induced oxidant production through activation of NADH/NADPH oxidase system (16) and increased the expression of chemokines such as monocyte chemoattractant protein-1 and IL-8 in the endothelial cells (13). In addition, LPC suppressed antithrombotic property of endothelial monolayer by inhibiting expression of tissue factor pathway inhibitor (15). LPC is a normal constituent of plasma and is generated by phospholipase A2-induced hydrolysis of membrane phosphatidylcholine. Increased plasma LPC levels are reported in several inflammatory diseases such as ischemia and asthma (see references cited in Ref. 4). LPC has been shown to be a pathological component of oxidized lipoproteins (LDL) in plasma and of atherosclerotic lesions (17). Interestingly, LPC is also released into plasma upon thrombin stimulation of endothelial cells (10). Thrombin is an established edemagenic mediator and increases endothelial permeability by the PKCα-RhoA pathway (2, 3, 11). In this regard, the Huang et al. (4) studies are interesting as they indicate that LPC can increase endothelial permeability directly and LPC generated by endothelial cells in response to edemagenic agents may exacerbate barrier-disruptive response. The homologies between signaling events activated by LPC and thrombin suggest that LPC may activate Rho and subsequent barrier disruption by activating the heterotrimeric G proteins Gq and G12/13. The orphan G protein-coupled receptor GPR4 expressed on endothelial cells has been suggested to induce LPC-mediated signaling events (8). Whether GPR4 couples to Gq and G12/13 in endothelial cells and induces Rho activation via these proteins remains to be tested.On the basis of evidence discussed above along with the findings of Huang et al. (4), LPC appears to be a proinflammatory mediator and may be intricately involved in disrupting endothelial barrier function resulting in inflammatory responses in the vessel wall. Surprisingly, LPC is described as being protective against lung vascular injury as extracellular application of 1 μM LPC prevented injury by N-formyl-methionyl-leucyl-phenylalanine-activated neutrophils in an isolated perfused lung model (6). In another study, subcutaneous administration of LPC activated neutrophils, which protected mice against sepsis induced by cecal ligaton and puncture or intraperitoneal injection of Escherichia coli (18). Along the same lines, a study shows that chronic septic patients who presumably have tissue inflammation and leaky endothelial barrier have lower plasma levels of LPC (1). It is possible that low plasma LPC levels are the result of activation of lipases. Together, these seemingly conflicting findings indicate that LPC effects on endothelium are complex and may depend on the integrity of endothelium. Whereas LPC disrupts barrier function in naïve endothelium, it has a protective role when the barrier is leaky. It is also possible that variable effects of LPC observed in cultured endothelial cells and in vivo experimental models could be very well due to differences in length and/or saturation state of fatty acid chain. Thus further studies are needed to understand the role of this “enigmatic” lysolipid in regulating endothelial permeability and inflammatory responses in cultured cells and in vivo models.REFERENCES1 Drobnik W, Liebisch G, Audebert FX, Frohlich D, Gluck T, Vogel P, Rothe G, and Schmitz G. Plasma ceramide and lysophosphatidylcholine inversely correlate with mortality in sepsis patients. J Lipid Res 44: 754–761, 2003.Crossref | PubMed | ISI | Google Scholar2 Dudek SM and Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol 91: 1487–1500, 2001.Link | ISI | Google Scholar3 Holinstat M, Mehta D, Kozasa T, Minshall RD, and Malik AB. Protein kinase Cα-induced p115RhoGEF phosphorylation signals endothelial cytoskeletal rearrangement. J Biol Chem 278: 28793–28798, 2003.Crossref | PubMed | ISI | Google Scholar4 Huang F, Subbaiah PV, Holian O, Zhang J, Johnson A, Gertzberg N, and Lum H. Lysophosphatidylcholine increases endothelial permeability: role of PKCα and RhoA cross talk. Am J Physiol Lung Cell Mol Physiol 289: L176–L185, 2005.Link | ISI | Google Scholar5 Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G, and Sternweis PC. p115 RhoGEF, a GTPase activating protein for Gα12 and Gα13. Science 280: 2109–2111, 1998.Crossref | PubMed | ISI | Google Scholar6 Lin P, Welch EJ, Gao XP, Malik AB, and Ye RD. Lysophosphatidylcholine modulates neutrophil oxidant production through elevation of cyclic AMP. J Immunol 174: 2981–2989, 2005.Crossref | PubMed | ISI | Google Scholar7 Lum H and Malik AB. Regulation of vascular endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 267: L223–L241, 1994.Link | ISI | Google Scholar8 Lum H, Qiao J, Walter RJ, Huang F, Subbaiah PV, Kim KS, and Holian O. Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells. Am J Physiol Heart Circ Physiol 285: H1786–H1789, 2003.Link | ISI | Google Scholar9 Lutz S, Freichel-Blomquist A, Yang Y, Rumenapp U, Jakobs KH, Schmidt M, and Wieland T. The guanine nucleotide exchange factor p63RhoGEF, a specific link between Gq/11-coupled receptor signaling and RhoA. J Biol Chem 280: 11134–11139, 2005.Crossref | PubMed | ISI | Google Scholar10 McHowat J and Corr PB. Thrombin-induced release of lysophosphatidylcholine from endothelial cells. J Biol Chem 268: 15605–15610, 1993.Crossref | PubMed | ISI | Google Scholar11 Mehta D, Rahman A, and Malik AB. Protein kinase C-α signals rho-guanine nucleotide dissociation inhibitor phosphorylation and rho activation and regulates the endothelial cell barrier function. J Biol Chem 276: 22614–22620, 2001.Crossref | PubMed | ISI | Google Scholar12 Miwa Y, Hirata K, Kawashima S, Akita H, and Yokoyama M. Lysophosphatidylcholine inhibits receptor-mediated Ca2+ mobilization in intact endothelial cells of rabbit aorta. Arterioscler Thromb Vasc Biol 17: 1561–1567, 1997.Crossref | PubMed | ISI | Google Scholar13 Murugesan G, Sandhya Rani MR, Gerber CE, Mukhopadhyay C, Ransohoff RM, Chisolm GM, and Kottke-Marchant K. Lysophosphatidylcholine regulates human microvascular endothelial cell expression of chemokines. J Mol Cell Cardiol 35: 1375–1384, 2003.Crossref | PubMed | ISI | Google Scholar14 Sah VP, Seasholtz TM, Sagi SA, and Brown JH. The role of Rho in G protein-coupled receptor signal transduction. Annu Rev Pharmacol Toxicol 40: 459–489, 2000.Crossref | PubMed | ISI | Google Scholar15 Sato N, Kokame K, Miyata T, and Kato H. Lysophosphatidylcholine decreases the synthesis of tissue factor pathway inhibitor in human umbilical vein endothelial cells. Thromb Haemost 79: 217–221, 1998.Crossref | PubMed | ISI | Google Scholar16 Takeshita S, Inoue N, Gao D, Rikitake Y, Kawashima S, Tawa R, Sakurai H, and Yokoyama M. Lysophosphatidylcholine enhances superoxide anions production via endothelial NADH/NADPH oxidase. J Atheroscler Thromb 7: 238–246, 2000.Crossref | PubMed | Google Scholar17 Wu R, Huang YH, Elinder LS, and Frostegard J. Lysophosphatidylcholine is involved in the antigenicity of oxidized LDL. Arterioscler Thromb Vasc Biol 18: 626–630, 1998.Crossref | PubMed | ISI | Google Scholar18 Yan JJ, Jung JS, Lee JE, Lee J, Huh SO, Kim HS, Jung KC, Cho JY, Nam JS, Suh HW, Kim YH, and Song DK. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat Med 10: 161–167, 2004.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: D. Mehta, Dept. of Pharmacology, Univ. of Illinois, College of Medicine, 835 S. Wolcott Ave., Chicago, IL 60612 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByUntargeted components and in vivo metabolites analyses of Polygonatum under different processing timesLWT, Vol. 173Gut microbiome in PCOS associates to serum metabolomics: a cross-sectional study23 December 2022 | Scientific Reports, Vol. 12, No. 1Phospholipases and Reactive Oxygen Species Derived Lipid Biomarkers in Healthy and Diseased Humans and Animals – A Focus on Lysophosphatidylcholine10 November 2021 | Frontiers in Physiology, Vol. 12Lysophosphatidylcholines and Chlorophyll-Derived Molecules from the Diatom Cylindrotheca closterium with Anti-Inflammatory Activity17 March 2020 | Marine Drugs, Vol. 18, No. 3Disulfide loop cleavage of Legionella pneumophila PlaA boosts lysophospholipase A activity24 November 2017 | Scientific Reports, Vol. 7, No. 1In Utero Exposure to Histological Chorioamnionitis Primes the Exometabolomic Profiles of Preterm CD4+ T Lymphocytes1 November 2017 | The Journal of Immunology, Vol. 199, No. 9Metabolomic profiles of current cigarette smokers22 August 2016 | Molecular Carcinogenesis, Vol. 56, No. 2Menthol Smokers: Metabolomic Profiling and Smoking Behavior8 January 2017 | Cancer Epidemiology, Biomarkers & Prevention, Vol. 26, No. 1Partitioning of lysolipids, fatty acids and their mixtures in aqueous lipid bilayers: Solute concentration/composition effectsBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 1838, No. 1Pathogenesis of type 1 diabetes: lessons from natural history studies of high‐risk individuals29 January 2013 | Annals of the New York Academy of Sciences, Vol. 1281, No. 1Membrane-perturbing effect of fatty acids and lysolipidsProgress in Lipid Research, Vol. 52, No. 1Integrated Model of Metabolism and Autoimmune Response in β-Cell Death and Progression to Type 1 Diabetes14 December 2012 | PLoS ONE, Vol. 7, No. 12Lysolipid containing liposomes for transendothelial drug delivery10 April 2012 | BMC Research Notes, Vol. 5, No. 1Serum Metabolic Profiling Study of Hepatocellular Carcinoma Infected with Hepatitis B or Hepatitis C Virus by Using Liquid Chromatography–Mass Spectrometry28 September 2012 | Journal of Proteome Research, Vol. 11, No. 11Type 1 Diabetes: Etiology, Immunology, and Therapeutic StrategiesTom L. 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