Enzymatic and receptor mediated effects of secretory phospholipase A2 on the pathophysiology of inflammatory diseases

  • Chad R. Marion
  • Alfred N. Fonteh
Part of the Progress in Inflammation Research book series (PIR)


Phospholipases A2 are enzymes that share the common attribute to hydrolyze fatty acids from the sn-2 position of glycerol phospholipids [1, 2, 3]. Groups I, II, V and X PLA2 are four sets of enzymes in a highly conserved family of secreted PLA2 found in mammals [4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. Other non-secreted PLA2 enzymes include group IV, cytosolic PLA2 (cPLA2) [15, 16, 17], group VI, calcium-independent PLA2 (iPLA2) [18, 19, 20, 21, 22] and groups VII and VIII, selective acetyl hydrolases [23, 24, 25, 26, 27, 28]. The secretory family of enzymes has a number of features that distinguish them from other PLA2 families including a relatively low molecular weight (~ 14 kDa), high disulfide bond content and a requirement for relatively high concentrations of calcium for maximal activation [29, 30]. In contrast, cytosolic enzymes are generally higher molecular weight proteins and require no calcium or very low calcium concentrations for optimal activation [18, 22]. Many sPLA2 isotypes are synthesized as proenzymes that contain a signal peptide sequence that facilitates its release from cells. sPLA2 isotypes have been studied extensively in mammals and in snake venoms, yet there is no clear understanding of their physiological and pathophysiological roles. Inspection of numerous publications dealing with sPLA2s reveals that they have potential to mediate a wide range of biological activities including:
  1. 1)

    Producers of AA that contributes to eicosanoid formation [31, 32, 33, 34, 35, 36]

  2. 2)

    Generation of lysophospholipids that contribute to electrophysiologic alteration that lead to arrythmogenesis in the heart or altered airway permeability and surfactant properities in the lung [37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48];

  3. 3)

    Potent antibacterial effects and implications in viral infections [49, 50, 51, 52, 53, 54];

  4. 4)

    Key components in glycerophospholipid digestion [55];

  5. 5)

    Serum markers and potential regulators of severe illnesses such as sepsis, shock, organ injury and pancreatitis, all of which are linked to the development of adult respiratory distress syndrome or multiple organ failure [56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75];

  6. 6)

    Regulators of platelet aggregation in hemorrhagic diseases [76, 77, 78];

  7. 7)

    Prevention of apoptosis of inflammatory cells and initiators of cell proliferation in several cancer cell lines [79, 80, 81, 82];

  8. 8)

    A potent modifying locus in intestinal tumorigenesis in mice that is absent in human [83];

  9. 9)

    Pro-inflammatory components in diseases such as rheumatoid arthritis and asthma [84, 85, 86, 87, 88, 89, 90, 91, 92, 93].



Mast Cell Mannose Receptor Cytosolic Phospholipase Secretory Phospholipase Receptor Mediate Effect 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Dennis EA (1997) The growing phospholipase A2superfamily of signal transduction enzymes Trends Biochem Sci 22: 1–2PubMedCrossRefGoogle Scholar
  2. 2.
    Murakami M, Nakatani Y, Atsumi G, Inoue K, Kudo I (1997) Regulatory functions of phospholipase A2. Crit Rev Immunol 17: 225–283PubMedCrossRefGoogle Scholar
  3. 3.
    Kramer RM (1993) Structure, function and regulation of mammalian phospholipases A2. Adv Second Messenger Phosphoprotein Res 28: 81–89PubMedGoogle Scholar
  4. 4.
    Kramer RM, Hession C, Johansen B, Hayes G, McGray P, Chow EP, Tizard R, Pepin-sky RB (1989) Structure and properties of a human non-pancreatic phospholipase A2. J Biol Chem 264: 5768–5775PubMedGoogle Scholar
  5. 5.
    Cupillard L, Koumanov K, Mattei MG, Lazdunski M, Lambeau G (1997) Cloning, chromosomal mapping, and expression of a novel human secretory phospholipase A2. J Biol Chem 272: 15745–15752PubMedCrossRefGoogle Scholar
  6. 6.
    Balboa MA, Balsinde J, Winstead MV, Tischfield JA, Dennis EA (1996) Novel group V phospholipase A2involved in arachidonic acid mobilization in murine P388D1 macrophages. J Biol Chem 271: 32381–32384PubMedCrossRefGoogle Scholar
  7. 7.
    Cho W, Han SK, Lee BI, Snitko Y, Dua R (1999) Purification and assay of mammalian group I and group Ha secretory phospholipase A2. Methods Mol Biol 109: 31–38PubMedGoogle Scholar
  8. 8.
    Han SK, Lee BI, Cho W (1997) Bacterial expression and characterization of human pan-creatic phospholipase A2. Biochim Biophys Acta 1346: 185–192PubMedCrossRefGoogle Scholar
  9. 9.
    Chen J, Shao C, Lazar V, Srivastava CH, Lee WH, Tischfield JA (1997) Localization of group IIc low molecular weight phospholipase A2mRNA to meiotic cells in the mouse. J Cell Biochem 64: 369–375PubMedCrossRefGoogle Scholar
  10. 10.
    Tischfield JA (1997) A reassessment of the low molecular weight phospholipase A2gene family in mammals. J Biol Chem 272: 17247–17250PubMedCrossRefGoogle Scholar
  11. 11.
    Seeds MC, Jones DF, Chilton FH, Bass DA (1998) Secretory and cytosolic phospholipases A2are activated during TNF priming of human neutrophils. Biochim Biophys Acta 1389: 273–284PubMedCrossRefGoogle Scholar
  12. 12.
    Shimbara S, Murakami M, Kambe T, Kudo I (1999) Comparison of recombinant types IIA, V and IIC phospholipase A2S, the three related mammalian secretory phospholipase A2isozymes [In Process Citation]. Adv Exp Med Biol 469: 209–214PubMedCrossRefGoogle Scholar
  13. 13.
    Gelb MH, Valentin E, Ghomashchi F, Lazdunski M, Lambeau G (2000) Cloning and recombinant expression of a structurally novel human secreted phospholipase A2. J Biol Chem 275: 39823–39826PubMedCrossRefGoogle Scholar
  14. 14.
    Tischfield JA (1997) A reassessment of the low molecular weight phospholipase A2gene family in mammals. J Biol Chem 272: 17247–17250PubMedCrossRefGoogle Scholar
  15. 15.
    Kramer RM, Roberts EF, Hyslop PA, Utterback BG, Hui KY, Jakubowski JA (1995) Differential activation of cytosolic phospholipase A2(cPLA2) by thrombin and thrombin receptor agonist peptide in human platelets. Evidence for activation of cPLA2independent of the mitogen-activated protein kinases ERK1/2. J Biol Chem 270: 14816–14823PubMedCrossRefGoogle Scholar
  16. 16.
    Sharp JD, White DL, Chiou XG, Goodson T, Gamboa GC, McClure D, Burgett S, Hoskins J, Skatrud PL, Sportsman JR (1991) Molecular cloning and expression of human Ca(2+)-sensitive cytosolic phospholipase A2. J Biol Chem 266: 14850–14853PubMedGoogle Scholar
  17. 17.
    Pickard RT, Strifler BA, Kramer RM, Sharp JD (1999) Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2. J Biol Chem 274: 8823–8831PubMedCrossRefGoogle Scholar
  18. 18.
    Ackermann EJ, Dennis EA (1995) Mammalian calcium-independent phospholipase A2. Biochim Biophys Acta 1259: 125–136PubMedCrossRefGoogle Scholar
  19. 19.
    Gross RW (1998) Activation of calcium-independent phospholipase A2by depletion of internal calcium stores. Biochem Soc Trans 26: 345–349PubMedGoogle Scholar
  20. 20.
    Hazen SL, Stuppy RJ, Gross RW (1990) Purification and characterization of canine myocardial cytosolic phospholipase A2. A calcium-independent phospholipase with absolute f1–2 regiospecificity for diradyl glycerophospholipids. J Biol Chem 265: 10622–10630PubMedGoogle Scholar
  21. 21.
    Portilla D, Crew MD, Grant D, Serrero G, Bates LM, Dai G, Sasner M, Cheng J, Buonanno A (1998) cDNA cloning and expression of a novel family of enzymes with calcium-independent phospholipase A2and lysophospholipase activities. J Am Soc Nephrol 9: 1178–1186PubMedGoogle Scholar
  22. 22.
    Underwood KW, Song C, Kriz RW, Chang XJ, Knopf JL, Lin LL (1998) A novel calcium-independent phospholipase A2cPLA2-gamma, that is prenylated and contains homology to cPLA2. J Biol Chem 273: 21926–21932PubMedCrossRefGoogle Scholar
  23. 23.
    Endo S, Inada K, Yamashita H, Takakuwa T, Nakae H, Kasai T, Kikuchi M, Ogawa M, Uchida K, Yoshida M (1994) Platelet-activating factor (PAF) acetylhydrolase activity, type II phospholipase A2and cytokine levels in patients with sepsis. Res Commun Chem Pathol Pharmacol 83: 289–295PubMedGoogle Scholar
  24. 24.
    MacPhee CH, Moores KE, Boyd HF, Dhanak D, Ife RJ, Leach CA, Leake DS, Milliner KJ, Patterson RA, Suckling KE et al (1999) Lipoprotein-associated phospholipase A2platelet-activating factor acetylhydrolase, generates two bioactive products during the oxidation of low-density lipoprotein: Use of a novel inhibitor. Biochem J 338 (Pt 2): 479–487PubMedCrossRefGoogle Scholar
  25. 25.
    Nijssen JG, Roosenboom CF, van den? BH (1986) Identification of a calcium-independent phospholipase A2in rat lung cytosol and differentiation from acetylhydrolase for 1-alkyl-2-acetyl-sn-glycero3-phosphocholine (PAF-acether). Biochim Biophys Acta 876: 611–618PubMedCrossRefGoogle Scholar
  26. 26.
    Soubeyrand S, Lazure C, Manjunath P (1998) Phospholipase A2from bovine seminal plasma is a platelet-activating factor acetylhydrolase. Biochem J 329 (Pt 1): 41–47PubMedGoogle Scholar
  27. 27.
    Tjoelker LW, Eberhardt C, Unger J, Trong HL, Zimmerman GA, McIntyre TM, Stafforini DM, Prescott SM, Gray PW (1995) Plasma platelet-activating factor acetylhydrolase is a secreted phospholipase A2with a catalytic triad. J Biol Chem 270: 25481–25487PubMedCrossRefGoogle Scholar
  28. 28.
    Touqui L, Herpin-Richard N, Gene RM, Jullian E, Aljabi D, Hamberger C, Vargaftig BB, Dessange JF (1994) Excretion of platelet activating factor-acetylhydrolase and phospholipase A2into nasal fluids after allergenic challenge: Possible role in the regulation of platelet activating factor release. J Allergy Clin Immunol 94: 109–119PubMedCrossRefGoogle Scholar
  29. 29.
    Fonteh AN, Bass DA, Marshall LA, Seeds M, Samet JM, Chilton FH (1994) Evidence that secretory phospholipase A2plays a role in arachidonic acid release and eicosanoid biosynthesis by mast cells. J Immunol 152: 5438–5446PubMedGoogle Scholar
  30. 30.
    Scott DL, Sigler PB (1994) Structure and catalytic mechanism of secretory phospholipases A2. Adv Protein Chem 45: 53–88PubMedCrossRefGoogle Scholar
  31. 31.
    Bomalaski JS, Baker DG, Brophy L, Resurreccion NV, Spilberg I, Muniain M, Clark MA (1989) A phospholipase A2-activating protein (PLAP) stimulates human neutrophil aggregation and release of lysosomal enzymes, superoxide, and eicosanoids. J Immunol 142: 3957–3962PubMedGoogle Scholar
  32. 32.
    Hsueh W, Tan XD, Qu XW, Sun XM, Gonzalez-Crussi F (1997) Injurious and protective mechanisms in the gut. Interaction of PAF, phospholipase A2eicosanoids, and nitric oxide synthase. Adv Exp Med Biol 407: 365–369PubMedGoogle Scholar
  33. 33.
    Kramer RM, Jakubowski JA, Deykin D (1988) Hydrolysis of 1-alkyl-2-arachidonoyl-snglycero-3-phosphocholine, a common precursor of platelet-activating factor and eicosanoids, by human platelet phospholipase A2. Biochim Biophys Acta 959: 269–279PubMedCrossRefGoogle Scholar
  34. 34.
    Nakae H, Endo S, Inada K, Yamashita H, Yamada Y, Takakuwa T, Kasai T, Ogawa M, Uchida K (1995) Plasma concentrations of type II phospholipase A2cytokines and eicosanoids in patients with burns. Burns 21: 422–426PubMedCrossRefGoogle Scholar
  35. 35.
    Fonteh AN, Bass DA, Marshall LA, Seeds M, Samet JM, Chilton FH (1994) Evidence that secretory phospholipase A2plays a role in arachidonic acid release and eicosanoid biosynthesis by mast cells. J Immunol 152: 5438–5446PubMedGoogle Scholar
  36. 36.
    Fonteh AN, Samet JM, Chilton FH (1995) Regulation of arachidonic acid, eicosanoid, and phospholipase A2levels in murine mast cells by recombinant stem cell factor. J Clin Invest 96: 1432–1439PubMedCrossRefGoogle Scholar
  37. 37.
    Balsinde J (2002) Roles of various phospholipases A2 in providing lysophospholipid acceptors for fatty acid phospholipid incorporation and remodelling. Biochem J 364: 695–702PubMedCrossRefGoogle Scholar
  38. 38.
    Metz SA (1986) Lysophosphatidylinositol, but not lysophosphatidic acid, stimulates insulin release. A possible role for phospholipase A2but not de novo synthesis of lysophospholipid in pancreatic islet function. Biochem Biophys Res Commun 138: 720–727PubMedCrossRefGoogle Scholar
  39. 39.
    Arbibe L, Koumanov K, Vial D, Rougeot C, Faure G, Havet N, Longacre S, Vargaftig BB, Bereziat G, Voelker DR et al (1998) Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2and inhibited by a direct surfactant protein A-phospholipase A2protein interaction. J Clin Invest 102: 1152–1160PubMedCrossRefGoogle Scholar
  40. 40.
    Edelson JD, Vadas P, Villar J, Mullen JB, Pruzanski W (1991) Acute lung injury induced by phospholipase A2. Structural and functional changes. Am Rev Respir Dis 143: 1102–1109PubMedGoogle Scholar
  41. 41.
    Fisher AB, Dodia C, Chander A, Jain M (1992) A competitive inhibitor of phospholipase A2decreases surfactant phosphatidylcholine degradation by the rat lung. Biochem J 288 (Pt 2): 407–411PubMedGoogle Scholar
  42. 42.
    Furue S, Mikawa K, Nishina K, Shiga M, Ueno M, Tomita Y, Kuwabara K, Teshirogi I, Ono T, Hori Y et al (2001) Therapeutic time-window of a group IIA phospholipase A2 inhibitor in rabbit acute lung injury: Correlation with lung surfactant protection. Crit Care Med 29: 719–727PubMedCrossRefGoogle Scholar
  43. 43.
    Koike K, Yamamoto Y, Hori Y, Ono T (2000) Group IIA phospholipase A2mediates lung injury in intestinal ischemia-reperfusion. Ann Surg 232: 90–97PubMedCrossRefGoogle Scholar
  44. 44.
    Liu L (1999) Regulation of lung surfactant secretion by phospholipase A2. J Cell Biochem 72: 103–110PubMedCrossRefGoogle Scholar
  45. 45.
    Chilton FH, Averill FJ, Hubbard WC, Fonteh AN, Triggiani M, Liu MC (1996) Antigen-induced generation of lyso-phospholipids in human airways. J Exp Med 183: 2235–2245PubMedCrossRefGoogle Scholar
  46. 46.
    De Windt LJ, Willems J, Roemen TH, Coumans WA, Reneman RS, Van Der Vusse GJ, Van Bilsen M (2001) Ischemic-reperfused isolated working mouse hearts: Membrane damage and type IIAphospholipase A2. Am J Physiol Heart Circ Physiol 280:H2572—H2580Google Scholar
  47. 47.
    Fletcher JE, Yang CC, Rosenberg P (1982) Basic phospholipase A2from Naja nigricollis snake venom: Phospholipid hydrolysis and effects on electrical and contractile activity of the rat heart. Toxicol Appl Pharmacol 66: 39–54PubMedCrossRefGoogle Scholar
  48. 48.
    Van Bilsen M, Van Der Vusse GJ (1995) Phospholipase-A2-dependent signalling in the heart. Cardiovasc Res 30: 518–529PubMedGoogle Scholar
  49. 49.
    Gronroos JO, Laine VJ, Nevalainen TJ (2002) Bactericidal group IIA phospholipase A2in serum of patients with bacterial infections. J Infect Dis 185: 1767–1772PubMedCrossRefGoogle Scholar
  50. 50.
    Juffrie M, Meer GM, Hack CE, Haasnoot K, Sutaryo Veerman AJ, Thijs LG (2001) Inflammatory mediators in dengue virus infection in children: Interleukin-6 and its relation to C-reactive protein and secretory phospholipase A2. Am J Trop Med Hyg 65: 70–75PubMedGoogle Scholar
  51. 51.
    Laine VJ, Grass DS, Nevalainen TJ (2000) Resistance of transgenic mice expressing human group II phospholipase A2to Escherichia coli infection. Infect Immun 68: 87–92PubMedCrossRefGoogle Scholar
  52. 52.
    Rintala EM, Nevalainen TJ (1993) Group II phospholipase A2in sera of febrile patients with microbiologically or clinically documented infections. Clin Infect Dis 17: 864–870PubMedCrossRefGoogle Scholar
  53. 53.
    Tunaz H, Park Y, Buyukguzel K, Bedick JC, Nor Aliza AR, Stanley DW (2003) Eicosanoids in insect immunity: Bacterial infection stimulates hemocytic phospholipase A2activity in tobacco hornworms. Arch Insect Biochem Physiol 52: 1–6PubMedCrossRefGoogle Scholar
  54. 54.
    Degousee N, Ghomashchi F, Stefanski E, Singer A, Smart BP, Borregaard N, Reithmeier R, Lindsay TF, Lichtenberger C, Reinisch W et al (2002) Groups IV, V, and X phospholipases A2s in human neutrophils: Role in eicosanoid production and gram-negative bacterial phospholipid hydrolysis. J Biol Chem 277: 5061–5073PubMedCrossRefGoogle Scholar
  55. 55.
    Borgstrom B (1980) Importance of phospholipids, pancreatic phospholipase A2and fatty acid for the digestion of dietary fat: In vitro experiments with the porcine enzymes. Gastroenterology 78: 954–962PubMedGoogle Scholar
  56. 56.
    Gijon MA, Perez C, Mendez E, Sanchez CM (1995) Phospholipase A2from plasma of patients with septic shock is associated with high-density lipoproteins and C3 anaphylatoxin: Some implications for its functional role. Biochem J 306 (Pt 1): 167–175PubMedGoogle Scholar
  57. 57.
    Gonzalez RJ, Moore EE, Ciesla DJ, Meng X, Biffl WL, Silliman CC (2001) Post-hemorrhagic shock mesenteric lymph lipids prime neutrophils for enhanced cytotoxicity via phospholipase A2. Shock 16: 218–222PubMedCrossRefGoogle Scholar
  58. 58.
    Green JA, Smith GM, Buchta R, Lee R, Ho KY, Rajkovic IA, Scott KF (1991) Circulating phospholipase A2activity associated with sepsis and septic shock is indistinguishable from that associated with rheumatoid arthritis. Inflammation 15: 355–367PubMedCrossRefGoogle Scholar
  59. 59.
    Marshall LA, Hall RH, Winkler JD, Badger A, Bolognese B, Roshak A, Flamberg PL, Sung CM, Chabot-Fletcher M, Adams JL et al (1995) SB 203347, an inhibitor of 14 kDa phospholipase A2alters human neutrophil arachidonic acid release and metabolism and prolongs survival in murine endotoxin shock. J Pharmacol Exp Ther 274: 1254–1262PubMedGoogle Scholar
  60. 60.
    Sorensen J, Kald B, Tagesson C, Lindahl M (1994) Platelet-activating factor and phospholipase A2in patients with septic shock and trauma. Intensive Care Med 20: 555–561PubMedCrossRefGoogle Scholar
  61. 61.
    Vadas P, Pruzanski W, Stefanski E (1988) Extracellular phospholipase A2: Causative agent in circulatory collapse of septic shock? Agents Actions 24: 320–325PubMedCrossRefGoogle Scholar
  62. 62.
    Vadas P, Pruzanski W (1991) Serum phospholipase A2values and septic shock. Crit Care Med 19: 988–990PubMedCrossRefGoogle Scholar
  63. 63.
    Xu D, Lu Q, Deitch EA (1995) Calcium and phospholipase A2appear to be involved in the pathogenesis of hemorrhagic shock-induced mucosal injury and bacterial translocation. Crit Care Med 23: 125–131PubMedCrossRefGoogle Scholar
  64. 64.
    Aufenanger J, Samman M, Quintel M, Fassbender K, Zimmer W, Bertsch T (2002) Pancreatic phospholipase A2activity in acute pancreatitis: A prognostic marker for early identification of patients at risk. Clin Chem Lab Med 40: 293–297PubMedCrossRefGoogle Scholar
  65. 65.
    Bird NC, Goodman AJ, Johnson AG (1989) Serum phospholipase A2activity in acute pancreatitis: An early guide to severity. Br J Surg 76: 731–732PubMedCrossRefGoogle Scholar
  66. 66.
    Buchler M, Malfertheiner P, Schadlich H, Nevalainen TJ, Friess H, Beger HG (1989) role of phospholipase A2in human acute pancreatitis. Gastroenterology 97: 1521–1526PubMedGoogle Scholar
  67. 67.
    Eskola JU, Nevalainen TJ (1986) Pancreatic phospholipase A2in human acute pancreatitis. Mater Med Pol 18: 132–135PubMedGoogle Scholar
  68. 68.
    Friess H, Shrikhande S, Riesle E, Kashiwagi M, Baczako K, Zimmermann A, Uhl W, Buchler MW (2001) Phospholipase A2isoforms in acute pancreatitis. Ann Surg 233: 204–212PubMedCrossRefGoogle Scholar
  69. 69.
    Gronroos JM, Nevalainen TJ (1992) Increased concentrations of synovial-type phospholipase A2in serum and pulmonary and renal complications in acute pancreatitis. Digestion 52: 232–236PubMedCrossRefGoogle Scholar
  70. 70.
    Kemppainen E, Hietaranta A, Puolakkainen P, Sainio V, Halttunen J, Haapiainen R, Kivilaakso E, Nevalainen T (1999) Bactericidallpermeability-increasing protein and group I and II phospholipase A2during the induction phase of human acute pancreatitis. Pancreas 18: 21–27PubMedCrossRefGoogle Scholar
  71. 71.
    Matsuda Y, Ogawa M, Nishijima J, Miyauchi K, Mori T (1986) Usefulness of determination of serum immunoreactive pancreatic phospholipase A2content for early identification of severe acute pancreatitis. Hepatogastroenterology 33: 214–216PubMedGoogle Scholar
  72. 72.
    Miura M, Endo S, Kaku LL, Inoue Y, Sato N, Wakabayshi G, Baba E, Katsuya H, Inada K, Sato S (2001) Plasma type II phospholipase A2levels in patients with acute pancreatitis. Res Commun Mol Pathol Pharmacol 109: 159–164PubMedGoogle Scholar
  73. 73.
    Nevalainen TJ (1989) The role of phospholipase A2in human acute pancreatitis. Klin Wochenschr 67: 180–182PubMedCrossRefGoogle Scholar
  74. 74.
    Schuppisser JP, Grotzinger U, Reichlin B, Tondelli P (1985) The role of phospholipase A2in respiratory failure of acute pancreatitis. Hely Chir Acta 51: 665–667Google Scholar
  75. 75.
    Touqui L, Arbibe L (1999) A role for phospholipase A2in ARDS pathogenesis. Mol Med Today 5: 244–249PubMedCrossRefGoogle Scholar
  76. 76.
    Blackwell GJ (1978) Phospholipase A2and platelet aggregation. Adv Prostaglandin Thromboxane Res 3: 137–142PubMedGoogle Scholar
  77. 77.
    Hazlett TL, Deems RA, Dennis EA (1990) Activation, aggregation, inhibition and the mechanism of phospholipase A2. Adv Exp Med Biol 279: 49–64PubMedCrossRefGoogle Scholar
  78. 78.
    Nakano T, Hanasaki K, Matsumoto S, Arita H (1988) Retinol induces platelet aggregation via activation of phospholipase A2. Biochem Biophys Res Commun 154: 1075–1080PubMedCrossRefGoogle Scholar
  79. 79.
    Atsumi G, Murakami M, Tajima M, Shimbara S, Hara N, Kudo I (1997) The perturbed membrane of cells undergoing apoptosis is susceptible to type II secretory phospholipase A2to liberate arachidonic acid. Biochim Biophys Acta 1349: 43–54PubMedCrossRefGoogle Scholar
  80. 80.
    Yagami T, Ueda K, Asakura K, Hayasaki-Kajiwara Y, Nakazato H, Sakaeda T, Hata S, Kuroda T, Takasu N, Hori Y (2002) Group IB secretory phospholipase A2induces neuronal cell death via apoptosis. J Neurochem 81: 449–461PubMedCrossRefGoogle Scholar
  81. 81.
    Yagami T, Ueda K, Asakura K, Hata S, Kuroda T, Sakaeda T, Takasu N, Tanaka K, Gemba T, Hori Y (2002) Human group IIA secretory phospholipase A2induces neuronal cell death via apoptosis. Mol Pharmacol 61: 114–126PubMedCrossRefGoogle Scholar
  82. 82.
    Fonteh AN, Marion CR, Barham BJ, Edens MB, Atsumi G, Samet JM, High KP, Chilton FH (2001) Enhancement of mast cell survival: A novel function of some secretory phospholipase A2isotypes. J Immunol 167: 4161–4171PubMedGoogle Scholar
  83. 83.
    Riggins GJ, Markowitz S, Wilson JK, Vogelstein B, Kinzler KW (1995) Absence of secretory phospholipase A2gene alterations in human colorectal cancer. Cancer Res 55: 5184–5186PubMedGoogle Scholar
  84. 84.
    Bomalaski JS, Clark MA (1990) Activation of phospholipase A2in rheumatoid arthritis. Adv Exp Med Biol 279: 231–238PubMedCrossRefGoogle Scholar
  85. 85.
    Bowton DL, Seeds MC, Fasano MB, Goldsmith B, Bass DA (1997) Phospholipase A2and arachidonate increase in bronchoalveolar lavage fluid after inhaled antigen challenge in asthmatics. Am J Respir Crit Care Med 155: 421–425PubMedGoogle Scholar
  86. 86.
    Busse W (1998) The role and contribution of leukotrienes in asthma. Ann Allergy Asthma Immunol 81: 17–26PubMedCrossRefGoogle Scholar
  87. 87.
    Calabrese C, Triggiani M, Marone G, Mazzarella G (2000) Arachidonic acid metabolism in inflammatory cells of patients with bronchial asthma. Allergy 55 (Suppl 61): 27–30PubMedCrossRefGoogle Scholar
  88. 88.
    Hurt-Camejo E, Paredes S, Masana L, Camejo G, Sartipy P, Rosengren B, Pedreno J, Vallve JC, Benito P, Wiklund 0 (2001) Elevated levels of small, low-density lipoprotein with high affinity for arterial matrix components in patients with rheumatoid arthritis: Possible contribution of phospholipase A2to this atherogenic profile. Arthritis Rheum 44: 2761–2767PubMedCrossRefGoogle Scholar
  89. 89.
    Komatsubara T, Tojo H, Ying Z, Tomita T, Ochi T, Okamoto M (1995) Serum phospholipase A2activity and immunoreactive group II phospholipase A2in rheumatoid arthritis. Clin Chim Acta 236: 109–112PubMedCrossRefGoogle Scholar
  90. 90.
    Kortekangas P, Aro HT, Nevalainen TJ (1994) Group II phospholipase A2in synovial fluid and serum in acute arthritis. Scand J Rheumatol 23: 68–72PubMedCrossRefGoogle Scholar
  91. 91.
    Kramer RM, Pepinsky RB (1991) Assay and purification of phospholipase A2from human synovial fluid in rheumatoid arthritis. Methods Enzymol 197: 373–381PubMedCrossRefGoogle Scholar
  92. 92.
    Lin MK, Farewell V, Vadas P, Bookman AA, Keystone EC, Pruzanski W (1996) Secretory phospholipase A2as an index of disease activity in rheumatoid arthritis. Prospective double blind study of 212 patients. J Rheumatol 23: 1162–1166PubMedGoogle Scholar
  93. 93.
    Pruzanski W, Vadas P (1988) Secretory synovial fluid phospholipase A2and its role in the pathogenesis of inflammation in arthritis. J Rheumatol 15: 1601–1603PubMedGoogle Scholar
  94. 94.
    Barbour SE, Dennis EA (1993) Antisense inhibition of group II phospholipase A2expression blocks the production of prostaglandin E2 by P388D1 cells. J Biol Chem 268: 21875–21882PubMedGoogle Scholar
  95. 95.
    Bayburt T, Yu BZ, Lin HK, Browning J, Jain MK, Gelb MH (1993) Human nonpancreatic secreted phospholipase A2: Interfacial parameters, substrate specificities, and competitive inhibitors. Biochemistry 32: 573–582PubMedCrossRefGoogle Scholar
  96. 96.
    Bernard P, Pintore M, Berthon JY, Chretien JR (2001) A molecular modeling and 3D QSAR study of a large series of indole inhibitors of human non-pancreatic secretory phospholipase A2. Eur J Med Chem 36: 1–19PubMedCrossRefGoogle Scholar
  97. 97.
    Blanchard SG, Andrews RC, Brown PJ, Gan LS, Lee FW, Sinhababu AK, Wheeler TN (1998) Discovery of bioavailable inhibitors of secretory phospholipase A2. Pharm Biotechnol 11: 445–463PubMedCrossRefGoogle Scholar
  98. 98.
    Flower R (1978) Steroidal anti-inflammatory drugs as inhibitors of phospholipase A2. Adv Prostaglandin Thromboxane Res 3: 105–112PubMedGoogle Scholar
  99. 99.
    Glaser KB (1995) Regulation of phospholipase A2enzymes: Selective inhibitors and their pharmacological potential. Adv Pharmacol 32: 31–66PubMedCrossRefGoogle Scholar
  100. 100.
    Hansford KA, Reid RC, Clark CI, Tyndall JD, Whitehouse MW, Guthrie T, McGeary RP, Schafer K, Martin JL, Fairlie DP (2003) D-tyrosine as a chiral precusor to potent inhibitors of human non-pancreatic secretory phospholipase A2(Ha) with anti-inflammatory activity. Chembiochem 4: 181–185PubMedCrossRefGoogle Scholar
  101. 101.
    Jain MK, Streb M, Rogers J, DeHaas GH (1984) Action of phospholipase A2on bilayers containing lysophosphatidylcholine analogs and the effect of inhibitors. Biochem Pharmacol 33: 2541–2551PubMedCrossRefGoogle Scholar
  102. 102.
    Kokotos G, Kotsovolou S, Six DA, Constantinou-Kokotou V, Beltzner CC, Dennis EA (2002) Novel 2-oxoamide inhibitors of human group IVA phospholipase A2. J Med Chem 45: 2891–2893PubMedCrossRefGoogle Scholar
  103. 103.
    Kokotos G, Constantinou-Kokotou V, Noula C, Nicolaou A, Gibbons WA (1996) Synthesis of lipidic amino acid and dipeptide inhibitors of human platelet phospholipase A2. Int J Pept Protein Res 48: 160–166PubMedCrossRefGoogle Scholar
  104. 104.
    Lappas M, Munns MJ, King RG, Rice GE (2001) Antisense oligonucleotide inhibition of type II phospholipase A2expression, release and activity in vitro. Placenta 22: 418–424CrossRefGoogle Scholar
  105. 105.
    Tanaka K, Arita H (1995) Secretory phospholipase A2inhibitors. Possible new anti-inflammatory agents. Agents Actions (Suppl) 46: 51–64Google Scholar
  106. 106.
    Kennedy BP, Payette P, Mudgett J, Vadas P, Pruzanski W, Kwan M, Tang C, Rancourt DE, Cromlish WA (1995) A natural disruption of the secretory group II phospholipase A2gene in inbred mouse strains. J Biol Chem 270: 22378–22385PubMedCrossRefGoogle Scholar
  107. 107.
    Lilja I, Smedh K, Olaison G, Sjodahl R, Tagesson C, Gustafson-Svard C (1995)Phospholipase A2gene expression and activity in histologically normal ileal mucosa and in Crohn’s ileitis. Gut 37: 380–385PubMedCrossRefGoogle Scholar
  108. 108.
    MacPhee M, Chepenik KP, Liddell RA, Nelson KK, Siracusa LD, Buchberg AM (1995) The secretory phospholipase A2 gene is a candidate for the Mom1 locus, a major modifier of ApcMin-induced intestinal neoplasia. Cell 81: 957–966PubMedCrossRefGoogle Scholar
  109. 109.
    Fox N, Song M, Schrementi J, Sharp JD, White DL, Snyder DW, Hartley LW, Carlson DG, Bach NJ, Dillard RD et al (1996) Transgenic model for the discovery of novel human secretory non-pancreatic phospholipase A2inhibitors. Eur J Pharmacol 308: 195–203PubMedCrossRefGoogle Scholar
  110. 110.
    Nevalainen TJ, Laine VJ, Grass DS (1997) Expression of human group II phospholipase A2in transgenic mice. J Histochem Cytochem 45: 1109–1119PubMedCrossRefGoogle Scholar
  111. 111.
    Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F, Komagata Y, Maki K, Ikuta K, Ouchi Y et al (1997) Role of cytosolic phospholipase A2in allergic response and parturition. Nature 390: 618–622PubMedCrossRefGoogle Scholar
  112. 112.
    Grass DS, Felkner RH, Chiang MY, Wallace RE, Nevalainen TJ, Bennett CF, Swanson ME (1996) Expression of human group II PLA2in transgenic mice results in epidermal hyperplasia in the absence of inflammatory infiltrate. j Clin Invest 97: 2233–2241PubMedCrossRefGoogle Scholar
  113. 113.
    Bingham CO III, Murakami M, Fujishima H, Hunt JE, Austen KF, Arm JP (1996) A heparin-sensitive phospholipase A2and prostaglandin endoperoxide synthase-2 are functionally linked in the delayed phase of prostaglandin D2 generation in mouse bone marrow-derived mast cells. J Biol Chem 271: 25936–25944PubMedCrossRefGoogle Scholar
  114. 114.
    Balsinde J, Barbour SE, Bianco ID, Dennis EA (1994) Arachidonic acid mobilization in P388D1 macrophages is controlled by two distinct Ca2+-dependent phospholipase A2enzymes. Proc Natl Acad Sci USA 91: 11060–11064PubMedCrossRefGoogle Scholar
  115. 115.
    Fonteh AN, Samet JM, Surette M, Reed W, Chilton FH (1998) Mechanisms that account for the selective release of arachidonic acid from intact cells by secretory phospholipase A2. Biochim Biophys Acta 1393: 253–266PubMedCrossRefGoogle Scholar
  116. 116.
    Fonteh AN, Atsumi G, LaPorte T, Chilton FH (2000) Secretory phospholipase A2receptor-mediated activation of cytosolic phospholipase A2in murine bone marrow-derived mast cells. J Immunol 165: 2773–2782PubMedGoogle Scholar
  117. 117.
    Bingham CO III, Fijneman RJ, Friend DS, Goddeau RP, Rogers RA, Austen KF, Arm JP (1999) Low molecular weight group IIA and group V phospholipase A2enzymes have different intracellular locations in mouse bone marrow-derived mast cells. J Biol Chem 274: 31476–31484PubMedCrossRefGoogle Scholar
  118. 118.
    Fujishima H, Sanchez Mejia RO, Bingham CO III, Lam BK, Sapirstein A, Bonventre JV, Austen KF, Arm JP (1999) Cytosolic phospholipase A2is essential for both the immediate and the delayed phases of eicosanoid generation in mouse bone marrow-derived mast cells. Proc Natl Acad Sci USA 96: 4803–4807PubMedCrossRefGoogle Scholar
  119. 119.
    Murakami M, Austen KF, Arm JP (1995) The immediate phase of c-sn-ligand stimulation of mouse bone marrow-derived mast cells elicits rapid leukotriene C4 generation through post-translational activation of cytosolic phospholipase A2and 5-lipoxygenase. J Exp Med 182: 197–206PubMedCrossRefGoogle Scholar
  120. 120.
    Reddy ST, Winstead MV, Tischfield JA, Herschman HR (1997) Analysis of the secretory phospholipase A2that mediates prostaglandin production in mast cells. J Biol Chem 272: 13591–13596PubMedCrossRefGoogle Scholar
  121. 121.
    Blom M, Tool AT, Weyer PC, Wolbink GJ, Brouwer MC, Calafat J, Egesten A, Knol EF, Hack CE, Roos D et al (1998) Human eosinophils express, relative to other circulating leukocytes, large amounts of secretory 14-kD phospholipase A2. Blood 91: 3037–3043PubMedGoogle Scholar
  122. 122.
    Hundley TR, Marshall LA, Hubbard WC, MacGlashan DW Jr (1998) Characteristics of arachidonic acid generation in human basophils: Relationship between the effects of inhibitors of secretory phospholipase A2activity and leukotriene C4 release. J Pharmacol Exp Ther 284: 847–857PubMedGoogle Scholar
  123. 123.
    Triggiani M, Granata F, Oriente A, De MV, Gentile M, Calabrese C, Palumbo C, Marone G (2000) Secretory phospholipases A2induce beta-glucuronidase release and IL-6 production from human lung macrophages. J Immunol 164: 4908–4915PubMedGoogle Scholar
  124. 124.
    Triggiani M, Granata F, Oriente A, Gentile M, Petraroli A, Balestrieri B, Marone G (2002) Secretory phospholipases A2induce cytokine release from blood and synovial fluid monocytes. Eur J Immunol 32: 67–76PubMedCrossRefGoogle Scholar
  125. 125.
    Triggiani M, Granata F, Balestrieri B, Petraroli A, Scalia G, Del Vecchio L, Marone G (2003) Secretory phospholipases A2activate selective functions in human eosinophils. J Immunol 170: 3279–3288PubMedGoogle Scholar
  126. 126.
    Galli SJ (2000) Mast cells and basophils. Curr Opin Hematol 7: 32–39PubMedCrossRefGoogle Scholar
  127. 127.
    Galli SJ (1993) New concepts about the mast cell. N Engl J Med 328: 257–265PubMedCrossRefGoogle Scholar
  128. 128.
    Gordon JR, Galli SJ (1991) Release of both preformed and newly synthesized tumor necrosis factor alpha (TNF-a)/cachectin by mouse mast cells stimulated via the Fc Chad R. Marion and Alfred N. Fonteh epsilon RI. A mechanism for the sustained action of mast cell-derived TNF-a during IgE-dependent biological responses. J Exp Med 174: 103–107Google Scholar
  129. 129.
    Wedemeyer J, Tsai M, Galli SJ (2000) Roles of mast cells and basophils in innate and acquired immunity. Curr Opin Immunol 12: 624–631PubMedCrossRefGoogle Scholar
  130. 130.
    Fonteh AN, Marion CR, Barham BJ, Edens MB, Atsumi G, Samet JM, High KP, Chilton FH (2001) Enhancement of mast cell survival: A novel function of some secretory phospholipase A2isotypes. J Immunol 167: 4161–4171PubMedGoogle Scholar
  131. 131.
    Nair X, Nettleton D, Clever D, Tramposch KM, Ghosh S, Franson RC (1993) Swine as a model of skin inflammation. Phospholipase A2-induced inflammation. Inflammation 17: 205–215PubMedCrossRefGoogle Scholar
  132. 132.
    Babu AS, Gowda TV (1994) Dissociation of enzymatic activity from toxic properties of the most basic phospholipase A2from Vipera russelli snake venom by guanidination of lysine residues. Toxicon 32: 749–752PubMedCrossRefGoogle Scholar
  133. 133.
    Arita H, Hanasaki K (1993) Physiological aspects of a high affinity binding site for pancreatic-type phospholipase A2. J Lipid Mediat 6: 217–222PubMedGoogle Scholar
  134. 134.
    Hanasaki K, Arita H (2002) Phospholipase A2receptor: A regulator of biological functions of secretory phospholipase A2. Prostaglandins Other Lipid Mediat 68–69: 71–82PubMedCrossRefGoogle Scholar
  135. 135.
    Hanasaki K, Arita H (1996) Structure and function of phospholipase A2receptor. Adv Exp Med Biol 416: 315–319PubMedGoogle Scholar
  136. 136.
    Ishizaki J, Kishino J, Teraoka H, Ohara O, Arita H (1993) Receptor-binding capability of pancreatic phospholipase A2is separable from its enzymatic activity. FEBS Lett 324: 349–352PubMedCrossRefGoogle Scholar
  137. 137.
    Lambeau G, Lazdunski M (1999) Receptors for a growing family of secreted phospholipases A2. Trends Pharmacol Sci 20: 162–170PubMedCrossRefGoogle Scholar
  138. 138.
    Lambeau G, Ancian P, Nicolas JP, Beiboer SH, Moinier D, Verheij H, Lazdunski M (1995) Structural elements of secretory phospholipases A2involved in the binding to Mtype receptors. J Biol Chem 270: 5534–5540PubMedCrossRefGoogle Scholar
  139. 139.
    Ancian P, Lambeau G, Mattei MG, Lazdunski M (1995) The human 180-kDa receptor for secretory phospholipases A2. Molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization. J Biol Chem 270: 8963–8970PubMedCrossRefGoogle Scholar
  140. 140.
    Hanasaki K, Yokota Y, Ishizaki J, Itoh T, Arita H (1997) Resistance to endotoxic shock in phospholipase A2receptor-deficient mice. J Biol Chem 272: 32792–32797PubMedCrossRefGoogle Scholar
  141. 141.
    Koduri RS, Gronroos JO, Laine VJ, Le Calvez C, Lambeau G, Nevalainen TJ, Gelb MH (2002) Bactericidal properties of human and murine groups I, II, V, X, and XII secreted phospholipases A2. J Biol Chem 277: 5849–5857PubMedCrossRefGoogle Scholar
  142. 142.
    Fourcade O, Simon MF, Viode C, Rugani N, Leballe F, Ragab A, Fournie B, Sarda L, Chap H (1995) Secretory phospholipase A2generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell 80: 919–927PubMedCrossRefGoogle Scholar
  143. 143.
    Bevers EM, Comfurius P, Zwaal RF (1983) Changes in membrane phospholipid distribution during platelet activation. Biochim Biophys Acta 736: 57–66PubMedCrossRefGoogle Scholar
  144. 144.
    Dekkers DW, Comfurius P, Bevers EM, Zwaal RF (2002) Comparison between Ca2+-induced scrambling of various fluorescently labelled lipid analogues in red blood cells. Biochem J 362: 741–747PubMedCrossRefGoogle Scholar
  145. 145.
    Fonteh AN, Chilton FH (1993) Mobilization of different arachidonate pools and their roles in the generation of leukotrienes and free arachidonic acid during immunologic activation of mast cells. J Immunol 150: 563–570PubMedGoogle Scholar
  146. 146.
    Fonteh AN, Chilton FH (1992) Rapid remodeling of arachidonate from phosphatidylcholine to phosphatidylethanolamine pools during mast cell activation. J Immunol 148: 1784–1791PubMedGoogle Scholar
  147. 147.
    Benveniste J, Chignard M, Le Couedic JP, Vargaftig BB (1982) Biosynthesis of platelet-activating factor (PAF-ACETHER) II. Involvement of phospholipase A2in the formation of PAF-ACETHER and lyso-PAF-ACETHER from rabbit platelets. Thromb Res 25: 375–385PubMedCrossRefGoogle Scholar
  148. 148.
    Blank ML, Fitzgerald V, Smith ZL, Snyder F (1995) Generation of the precursor (lysoPAF) of platelet-activating factor via a CoA-dependent transacylase. Biochem Biophys Res Commun 210: 1052–1058PubMedCrossRefGoogle Scholar
  149. 149.
    Snyder F, Lee TC, Blank M, Malone B, Woodard D, Robinson M (1985) Platelet-activating factor: Alternate pathways of biosynthesis, mechanism of inactivation, and reacylation of lyso-PAF with arachidonate. Adv Prostaglandin Thromboxane Leukot Res 15: 693–696PubMedGoogle Scholar
  150. 150.
    East L, Isacke CM (2002) The mannose receptor family. Biochim Biophys Acta 1572: 364–386PubMedCrossRefGoogle Scholar
  151. 151.
    Durstin M, Durstin S, Molski TF, Becker EL, Sha’afi RI (1994) Cytoplasmic phospholipase A2translocates to membrane fraction in human neutrophils activated by stimuli that phosphorylate mitogen-activated protein kinase. Proc Natl Acad Sci USA 91: 3142–3146PubMedCrossRefGoogle Scholar
  152. 152.
    Gordon RD, Leighton IA, Campbell DG, Cohen P, Creaney A, Wilton DC, Masters DJ, Ritchie GA, Mott R, Taylor 1W et al (1996) Cloning and expression of cystolic phospholipase A2(cPLA2) and a naturally occurring variant. Phosphorylation of Ser505 of recombinant cPLA2by p42 mitogen-activated protein kinase results in an increase in specific activity. Eur J Biochem 238: 690–697PubMedCrossRefGoogle Scholar
  153. 153.
    Hazan-Halevy I, Levy R (2000) Activation of cytosolic phospholipase A2by opsonized zymosan in human neutrophils requires both ERK and p38 MAP-kinase. Adv Exp Med Biol 479: 115–123PubMedCrossRefGoogle Scholar
  154. 154.
    Hefner Y, Borsch-Haubold AG, Murakami M, Wilde JI, Pasquet S, Schieltz D, Ghomashchi F, Yates JR III, Armstrong CG, Paterson A et al (2000) Serine 727 phosphorylation and activation of cytosolic phospholipase A2by MNK1-related protein kinases. J Biol Chem 275: 37542–37551PubMedCrossRefGoogle Scholar
  155. 155.
    Kramer RM, Roberts EF, Hyslop PA, Utterback BG, Hui KY, Jakubowski JA (1995) Differential activation of cytosolic phospholipase A2(cPLA2) by thrombin and thrombin receptor agonist peptide in human platelets. Evidence for activation of cPLA2independent of the mitogen-activated protein kinases ERK1/2. J Biol Chem 270: 14816–14823PubMedCrossRefGoogle Scholar
  156. 156.
    Kramer RM, Roberts EF, Um SL, Borsch-Haubold AG, Watson SP, Fisher MJ, Jakubowski JA (1996) p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2(cPLA2) in thrombin-stimulated platelets. Evidence that prolinedirected phosphorylation is not required for mobilization of arachidonic acid by cPLA2. J Biol Chem 271: 27723–27729PubMedCrossRefGoogle Scholar
  157. 157.
    Kawakami T, Galli SJ (2002) Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol 2: 773–786PubMedCrossRefGoogle Scholar
  158. 158.
    Hata D, Kawakami Y, Inagaki N, Lantz CS, Kitamura T, Khan WN, Maeda-Yamamoto M, Miura T, Han W, Hartman SE et al (1998) Involvement of Bruton’s tyrosine kinase in Fc epsilon RI-dependent mast cell degranulation and cytokine production. J Exp Med 187: 1235–1247PubMedCrossRefGoogle Scholar
  159. 159.
    Petro JB, Khan WN (2001) Phospholipase C-gamma 2 couples Bruton’s tyrosine kinase to the NF-kappa B signaling pathway in B lymphocytes. J Biol Chem 276: 1715–1719PubMedCrossRefGoogle Scholar
  160. 160.
    Tsai M, Chen RH, Tam SY, Blenis J, Galli SJ (1993) Activation of MAP kinases, pp90rsk and pp70-S6 kinases in mouse mast cells by signaling through the c-kit receptor tyrosine kinase or Fc epsilon RI: Rapamycin inhibits activation of pp70-S6 kinase and proliferation in mouse mast cells. Eur J Immunol 23: 3286–3291PubMedCrossRefGoogle Scholar
  161. 161.
    Galli SJ, Tsai M, Wershil BK (1993) The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others. Am J Pathol 142: 965–974PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2004

Authors and Affiliations

  • Chad R. Marion
    • 1
  • Alfred N. Fonteh
    • 2
  1. 1.Infectious Diseases, Department of Internal MedicineWake Forest University School of MedicineWinston-SalemUSA
  2. 2.Molecular Neurology ProgramHuntington Medical Research InstitutesPasadenaUSA

Personalised recommendations