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Immunologic Research

, Volume 58, Issue 2–3, pp 387–393 | Cite as

Leukotrienes in pulmonary arterial hypertension

  • Wen Tian
  • Xinguo Jiang
  • Yon K. Sung
  • Jin Qian
  • Ke Yuan
  • Mark R. Nicolls
IMMUNOLOGY AT STANFORD UNIVERSITY

Abstract

Leukotrienes (LTs) are lipid mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism and are markers and mediators of pulmonary inflammation. Research over the past two decades has established that LTs modulate inflammation in pulmonary arterial hypertension (PAH). The purpose of this review was to summarize the current knowledge of LTs in the pathophysiology of PAH and to highlight a recent study that advances our understanding of how leukotriene B4 (LTB4) specifically contributes to pulmonary vascular remodeling. The results of these studies suggest that pharmacological inhibition of LT pathways, especially LTB4, has high potential for the treatment of PAH.

Keywords

Leukotriene Pulmonary arterial hypertension Vascular remodeling Inflammation 5-Lipoxygenase 

Notes

Conflict of interest

WT and MRN and Stanford University (OTL #S11-438) have a patent pending concerning the use of LTB4 antagonists for the treatment of PAH.

References

  1. 1.
    Benza RL, Miller DP, Gomberg-Maitland M, Frantz RP, Foreman AJ, Coffey CS, Frost A, Barst RJ, Badesch DB, Elliott CG, et al. Predicting survival in pulmonary arterial hypertension: insights from the registry to evaluate early and long-term pulmonary arterial hypertension disease management (REVEAL). Circulation. 2010;122(2):164–72.CrossRefPubMedGoogle Scholar
  2. 2.
    Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997;336(2):111–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Rubin LJ. Pathology and pathophysiology of primary pulmonary hypertension. Am J Cardiol. 1995;75(3):51A–4A.CrossRefPubMedGoogle Scholar
  4. 4.
    Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, Gaine S. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol. 2004;43(12 Suppl S):40S–7S.CrossRefPubMedGoogle Scholar
  5. 5.
    Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of disease: pulmonary arterial hypertension. Nat Rev Cardiol. 2011;8(8):443–55.CrossRefPubMedGoogle Scholar
  6. 6.
    Hassoun PM, Mouthon L, Barbera JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, et al. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol. 2009;54(1 Suppl):S10–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Nicolls MR, Taraseviciene-Stewart L, Rai PR, Badesch DB, Voelkel NF. Autoimmunity and pulmonary hypertension: a perspective. Eur Respir J. 2005;26(6):1110–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Taraseviciene-Stewart L, Nicolls MR, Kraskauskas D, Scerbavicius R, Burns N, Cool C, Wood K, Parr JE, Boackle SA, Voelkel NF. Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med. 2007;175(12):1280–9.PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Peters-Golden M, Henderson WR Jr. Leukotrienes. New Engl J Med. 2007;357(18):1841–54.CrossRefPubMedGoogle Scholar
  10. 10.
    Peters-Golden M, Canetti C, Mancuso P, Coffey MJ. Leukotrienes: underappreciated mediators of innate immune responses. J Immunol. 2005;174(2):589–94.CrossRefPubMedGoogle Scholar
  11. 11.
    Peters-Golden M, Brock TG. 5-lipoxygenase and FLAP. Prostaglandins Leukot Essent Fatty Acids. 2003;69(2–3):99–109.CrossRefPubMedGoogle Scholar
  12. 12.
    Peters-Golden M, Brock TG. Intracellular compartmentalization of leukotriene biosynthesis. Am J Respir Crit Care Med. 2000;161(2 Pt 2):S36–40.CrossRefPubMedGoogle Scholar
  13. 13.
    Samuelsson B, Funk CD. Enzymes involved in the biosynthesis of leukotriene B4. J Biol Chem. 1989;264(33):19469–72.PubMedGoogle Scholar
  14. 14.
    Fitzpatrick FA, Liggett WF, Wynalda MA. Albumin-eicosanoid interactions. A model system to determine their attributes and inhibition. J Biol Chem. 1984;259(5):2722–7.PubMedGoogle Scholar
  15. 15.
    Yokomizo T, Uozumi N, Takahashi T, Kume K, Izumi T, Shimizu T. Leukotriene A4 hydrolase and leukotriene B4 metabolism. J Lipid Mediat Cell Signal. 1995;12(2–3):321–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Shimizu T, Izumi T, Seyama Y, Tadokoro K, Radmark O, Samuelsson B. Characterization of leukotriene A4 synthase from murine mast cells: evidence for its identity to arachidonate 5-lipoxygenase. Proc Natl Acad Sci USA. 1986;83(12):4175–9.PubMedCentralCrossRefPubMedGoogle Scholar
  17. 17.
    Izumi T, Minami M, Ohishi N, Bito H, Shimizu T. Site-directed mutagenesis of leukotriene A4 hydrolase: distinction of leukotriene A4 hydrolase and aminopeptidase activities. J Lipid Mediat. 1993;6(1–3):53–8.PubMedGoogle Scholar
  18. 18.
    Minami M, Ohno S, Kawasaki H, Radmark O, Samuelsson B, Jornvall H, Shimizu T, Seyama Y, Suzuki K. Molecular cloning of a cDNA coding for human leukotriene A4 hydrolase. Complete primary structure of an enzyme involved in eicosanoid synthesis. J Biol Chem. 1987;262(29):13873–6.PubMedGoogle Scholar
  19. 19.
    Shimizu T, Izumi T, Ohishi N, Seyama Y, Kitamura S. Biosynthesis and further transformations of leukotriene A4. Adv Prostaglandin Thromboxane Leukot Res. 1987;17A:64–8.PubMedGoogle Scholar
  20. 20.
    Hammerstrom S, Samuelsson B. Detection of leukotriene A4 as an intermediate in the biosynthesis of leukotrienes C4 and D4. FEBS Lett. 1980;122(1):83–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science. 2001;294(5548):1871–5.CrossRefPubMedGoogle Scholar
  22. 22.
    Radmark O, Malmsten C, Samuelsson B. Leukotriene A4: enzymatic conversion to leukotriene C4. Biochem Biophys Res Commun. 1980;96(4):1679–87.CrossRefPubMedGoogle Scholar
  23. 23.
    Orning L, Hammarstrom S. Inhibition of leukotriene C and leukotriene D biosynthesis. J Biol Chem. 1980;255(17):8023–6.PubMedGoogle Scholar
  24. 24.
    Malmsten CL, Palmblad J, Uden AM, Radmark O, Engstedt L, Samuelsson B. Leukotriene B4: a highly potent and stereospecific factor stimulating migration of polymorphonuclear leukocytes. Acta Physiol Scand. 1980;110(4):449–51.CrossRefPubMedGoogle Scholar
  25. 25.
    Sha’afi RI, Naccache PH, Molski TF, Borgeat P, Goetzl EJ. Cellular regulatory role of leukotriene B4: its effects on cation homeostasis in rabbit neutrophils. J Cell Physiol. 1981;108(3):401–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Henderson WR, Jorg A, Klebanoff SJ. Eosinophil peroxidase-mediated inactivation of leukotrienes B4, C4, and D4. J Immunol. 1982;128(6):2609–13.PubMedGoogle Scholar
  27. 27.
    Czarnetzki BM. Is eosinophil chemotactic factor identical with leukotriene B? Int Arch Allergy Appl Immunol. 1982;67(2):181–3.CrossRefPubMedGoogle Scholar
  28. 28.
    Jorg A, Henderson WR, Murphy RC, Klebanoff SJ. Leukotriene generation by eosinophils. J Exp Med. 1982;155(2):390–402.CrossRefPubMedGoogle Scholar
  29. 29.
    Murphy RC, Mathews WR. Purification and characterization of leukotrienes from mastocytoma cells. Methods Enzymol. 1982;86:409–16.CrossRefPubMedGoogle Scholar
  30. 30.
    Holgate ST, Church MK. Control of mediator release from mast cells. Clin Allergy. 1982;12(Suppl):5–13.PubMedGoogle Scholar
  31. 31.
    Hsueh W, Sun FF. Leukotriene B4 biosynthesis by alveolar macrophages. Biochem Biophys Res Commun. 1982;106(4):1085–91.CrossRefPubMedGoogle Scholar
  32. 32.
    Doig MV, Ford-Hutchinson AW. The production and characterisation of products of the lipoxygenase enzyme system released by rat peritoneal macrophages. Prostaglandins. 1980;20(6):1007–19.CrossRefPubMedGoogle Scholar
  33. 33.
    Fels AO, Pawlowski NA, Cramer EB, King TK, Cohn ZA, Scott WA. Human alveolar macrophages produce leukotriene B4. Proc Natl Acad Sci USA. 1982;79(24):7866–70.PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Hui Y, Funk CD. Cysteinyl leukotriene receptors. Biochem Pharmacol. 2002;64(11):1549–57.CrossRefPubMedGoogle Scholar
  35. 35.
    Yokomizo T, Masuda K, Kato K, Toda A, Izumi T, Shimizu T. Leukotriene B4 receptor. Cloning and intracellular signaling. Am J Respir Crit Care Med. 2000;161(2 Pt 2):S51–5.CrossRefPubMedGoogle Scholar
  36. 36.
    Izumi T, Yokomizo T, Igarashi T, Shimizu T. Molecular cloning and characterization of leukotriene B4 receptor. Adv Exp Med Biol. 1999;469:237–44.CrossRefPubMedGoogle Scholar
  37. 37.
    Crooke ST, Mattern M, Sarau HM, Winkler JD, Balcarek J, Wong A, Bennett CF. The signal transduction system of the leukotriene D4 receptor. Trends Pharmacol Sci. 1989;10(3):103–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Cristol JP, Provencal B, Sirois P. Leukotriene receptors. J Recept Res. 1989;9(4–5):341–67.PubMedGoogle Scholar
  39. 39.
    Metters KM. Leukotriene receptors. J Lipid Mediat Cell Signal. 1995;12(2–3):413–27.CrossRefPubMedGoogle Scholar
  40. 40.
    Lipworth BJ. Leukotriene-receptor antagonists. Lancet. 1999;353(9146):57–62.CrossRefPubMedGoogle Scholar
  41. 41.
    Voelkel NF, Tuder RM, Wade K, Hoper M, Lepley RA, Goulet JL, Koller BH, Fitzpatrick F. Inhibition of 5-lipoxygenase-activating protein (FLAP) reduces pulmonary vascular reactivity and pulmonary hypertension in hypoxic rats. J Clin Invest. 1996;97(11):2491–8.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Wright L, Tuder RM, Wang J, Cool CD, Lepley RA, Voelkel NF. 5-Lipoxygenase and 5-lipoxygenase activating protein (FLAP) immunoreactivity in lungs from patients with primary pulmonary hypertension. Am J Respir Crit Care Med. 1998;157(1):219–29.CrossRefPubMedGoogle Scholar
  43. 43.
    Jones JE, Walker JL, Song Y, Weiss N, Cardoso WV, Tuder RM, Loscalzo J, Zhang YY. Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol. 2004;286(5):H1775–84.CrossRefPubMedGoogle Scholar
  44. 44.
    Runo JR, Vnencak-Jones CL, Prince M, Loyd JE, Wheeler L, Robbins IM, Lane KB, Newman JH, Johnson J, Nichols WC, et al. Pulmonary veno-occlusive disease caused by an inherited mutation in bone morphogenetic protein receptor II. Am J Respir Crit Care Med. 2003;167(6):889–94.CrossRefPubMedGoogle Scholar
  45. 45.
    Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez MA, Martensson G, Galie N, Manes A, Corris P, Simonneau G, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat. 2006;27(2):212–3.CrossRefPubMedGoogle Scholar
  46. 46.
    Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, Coccolo F, Ventura C, Phillips JA 3rd, Knowles JA, et al. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol. 2004;43(12 Suppl S):33S–9S.CrossRefPubMedGoogle Scholar
  47. 47.
    Takahashi H, Goto N, Kojima Y, Tsuda Y, Morio Y, Muramatsu M, Fukuchi Y. Downregulation of type II bone morphogenetic protein receptor in hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol. 2006;290(3):L450–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Song Y, Jones JE, Beppu H, Keaney JF Jr, Loscalzo J, Zhang YY. Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice. Circulation. 2005;112(4):553–62.PubMedCentralCrossRefPubMedGoogle Scholar
  49. 49.
    Radmark O, Samuelsson B. Regulation of the activity of 5-lipoxygenase, a key enzyme in leukotriene biosynthesis. Biochem Biophys Res Commun. 2010;396(1):105–10.CrossRefPubMedGoogle Scholar
  50. 50.
    Werz O, Klemm J, Samuelsson B, Radmark O. 5-lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases. Proc Natl Acad Sci USA. 2000;97(10):5261–6.PubMedCentralCrossRefPubMedGoogle Scholar
  51. 51.
    Radmark O, Samuelsson B. 5-Lipoxygenase: mechanisms of regulation. J Lipid Res. 2009;50(Suppl):S40–5.PubMedCentralPubMedGoogle Scholar
  52. 52.
    Werz O, Szellas D, Steinhilber D, Radmark O. Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). J Biol Chem. 2002;277(17):14793–800.CrossRefPubMedGoogle Scholar
  53. 53.
    Tabata T, Ono S, Song C, Noda M, Suzuki S, Tanita T, Fujimura S. Role of leukotriene B4 in monocrotaline-induced pulmonary hypertension. Nihon Kyobu Shikkan Gakkai Zasshi. 1997;35(2):160–6.PubMedGoogle Scholar
  54. 54.
    Tian W, Jiang X, Tamosiuniene R, Sung YK, Qian J, Dhillon G, Gera L, Farkas L, Rabinovitch M, Zamanian RT, et al. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013;5(200):200ra117.PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Chalfant CE, Spiegel S. Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci. 2005;118(Pt 20):4605–12.CrossRefPubMedGoogle Scholar
  56. 56.
    Wang L, Dudek SM. Regulation of vascular permeability by sphingosine 1-phosphate. Microvasc Res. 2009;77(1):39–45.PubMedCentralCrossRefPubMedGoogle Scholar
  57. 57.
    Rodriguez C, Gonzalez-Diez M, Badimon L, Martinez-Gonzalez J. Sphingosine-1-phosphate: a bioactive lipid that confers high-density lipoprotein with vasculoprotection mediated by nitric oxide and prostacyclin. Thromb Haemost. 2009;101(4):665–73.PubMedGoogle Scholar
  58. 58.
    Gonzalez-Diez M, Rodriguez C, Badimon L, Martinez-Gonzalez J. Prostacyclin induction by high-density lipoprotein (HDL) in vascular smooth muscle cells depends on sphingosine 1-phosphate receptors: effect of simvastatin. Thromb Haemost. 2008;100(1):119–26.PubMedGoogle Scholar
  59. 59.
    Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J, Griffiths R, Barbour SE, Milstien S, Spiegel S. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J. 2008;22(8):2629–38.PubMedCentralCrossRefPubMedGoogle Scholar
  60. 60.
    Heller EA, Liu E, Tager AM, Sinha S, Roberts JD, Koehn SL, Libby P, Aikawa ER, Chen JQ, Huang P, et al. Inhibition of atherogenesis in BLT1-deficient mice reveals a role for LTB4 and BLT1 in smooth muscle cell recruitment. Circulation. 2005;112(4):578–86.CrossRefPubMedGoogle Scholar
  61. 61.
    Orning L, Krivi G, Fitzpatrick FA. Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. J Biol Chem. 1991;266(3):1375–8.PubMedGoogle Scholar
  62. 62.
    Muskardin DT, Voelkel NF, Fitzpatrick FA. Modulation of pulmonary leukotriene formation and perfusion pressure by bestatin, an inhibitor of leukotriene A4 hydrolase. Biochem Pharmacol. 1994;48(1):131–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Ota K, Kurita S, Yamada K, Masaoka T, Uzuka Y, Ogawa N. Immunotherapy with bestatin for acute nonlymphocytic leukemia in adults. Cancer Immunol Immunother. 1986;23(1):5–10.CrossRefPubMedGoogle Scholar
  64. 64.
    Ota K, Uzuka Y. Clinical trials of bestatin for leukemia and solid tumors. Biotherapy. 1992;4(3):205–14.CrossRefPubMedGoogle Scholar
  65. 65.
    Rao NL, Dunford PJ, Xue X, Jiang X, Lundeen KA, Coles F, Riley JP, Williams KN, Grice CA, Edwards JP, et al. Anti-inflammatory activity of a potent, selective leukotriene A4 hydrolase inhibitor in comparison with the 5-lipoxygenase inhibitor zileuton. J Pharmacol Exp Ther. 2007;321(3):1154–60.CrossRefPubMedGoogle Scholar
  66. 66.
    Whittle BJ, Varga C, Berko A, Horvath K, Posa A, Riley JP, Lundeen KA, Fourie AM, Dunford PJ. Attenuation of inflammation and cytokine production in rat colitis by a novel selective inhibitor of leukotriene A4 hydrolase. Br J Pharmacol. 2008;153(5):983–91.PubMedCentralCrossRefPubMedGoogle Scholar
  67. 67.
    Marder P, Spaethe SM, Froelich LL, Cerimele BJ, Petersen BH, Tanner T, Lucas RA. Inhibition of ex vivo neutrophil activation by oral LY293111, a novel leukotriene B4 receptor antagonist. Br J Clin Pharmacol. 1996;42(4):457–64.PubMedCentralCrossRefPubMedGoogle Scholar
  68. 68.
    Marder P, Sawyer JS, Froelich LL, Mann LL, Spaethe SM. Blockade of human neutrophil activation by 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]propoxy]phenoxy]benzoic acid (LY293111), a novel leukotriene B4 receptor antagonist. Biochem Pharmacol. 1995;49(11):1683–90.CrossRefPubMedGoogle Scholar
  69. 69.
    Feinmark SJ, Cannon PJ. Endothelial cell leukotriene C4 synthesis results from intercellular transfer of leukotriene A4 synthesized by polymorphonuclear leukocytes. J Biol Chem. 1986;261(35):16466–72.PubMedGoogle Scholar
  70. 70.
    Tamosiuniene R, Nicolls MR. Regulatory T cells and pulmonary hypertension. Trends Cardiovasc Med. 2011;21(6):166–71.PubMedCentralCrossRefPubMedGoogle Scholar
  71. 71.
    Tamosiuniene R, Tian W, Dhillon G, Wang L, Sung YK, Gera L, Patterson AJ, Agrawal R, Rabinovitch M, Ambler K, et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res. 2011;109(8):867–79.PubMedCentralCrossRefPubMedGoogle Scholar
  72. 72.
    Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10(12):849–59.PubMedCentralCrossRefPubMedGoogle Scholar
  73. 73.
    Rubin LJ. Treatment of pulmonary arterial hypertension due to scleroderma: challenges for the future. Rheum Dis Clin North Am. 2008;34(1):191–7 viii.CrossRefPubMedGoogle Scholar
  74. 74.
    Chin KM, Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol. 2008;51(16):1527–38.CrossRefPubMedGoogle Scholar
  75. 75.
    Smedegard G, Hedqvist P, Dahlen SE, Revenas B, Hammarstrom S, Samuelsson B. Leukotriene C4 affects pulmonary and cardiovascular dynamics in monkey. Nature. 1982;295(5847):327–9.CrossRefPubMedGoogle Scholar
  76. 76.
    Weiss JW, Drazen JM, Coles N, McFadden ER Jr, Weller PF, Corey EJ, Lewis RA, Austen KF. Bronchoconstrictor effects of leukotriene C in humans. Science. 1982;216(4542):196–8.CrossRefPubMedGoogle Scholar
  77. 77.
    Hanna CJ, Bach MK, Pare PD, Schellenberg RR. Slow-reacting substances (leukotrienes) contract human airway and pulmonary vascular smooth muscle in vitro. Nature. 1981;290(5804):343–4.CrossRefPubMedGoogle Scholar
  78. 78.
    Stenmark KR, James SL, Voelkel NF, Toews WH, Reeves JT, Murphy RC. Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension. New Engl J Med. 1983;309(2):77–80.CrossRefPubMedGoogle Scholar
  79. 79.
    Dobyns EL, Wescott JY, Kennaugh JM, Ross MN, Stenmark KR. Eicosanoids decrease with successful extracorporeal membrane oxygenation therapy in neonatal pulmonary hypertension. Am J Respir Crit Care Med. 1994;149(4 Pt 1):873–80.CrossRefPubMedGoogle Scholar
  80. 80.
    Dingemanse J, Sidharta PN, Maddrey WC, Rubin LJ, Mickail H. Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opin Drug Saf. 2013. doi: 10.1517/14740338.2014.859674.

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Wen Tian
    • 1
  • Xinguo Jiang
    • 1
  • Yon K. Sung
    • 1
  • Jin Qian
    • 1
  • Ke Yuan
    • 2
  • Mark R. Nicolls
    • 1
  1. 1.VA Palo Alto Health Care SystemStanford UniversityPalo AltoUSA
  2. 2.Stanford University School of MedicineStanfordUSA

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