Skip to main content
SpringerLink
Log in

Nitric Oxide and Leukocyte Adhesion: Experience with NO Inhibitors, NO Donors and iNOS-Deficient Mice

  • Conference paper
Shock, Sepsis, and Organ Failure

  • 75 Accesses

Abstract

Inflammation is a normal response to infection and/or cellular and tissue injury, however following ischemia/reperfusion and sepsis, an over-exuberant or inappropriate inflammatory response leads to deleterious consequences to host tissue. The key feature and underlying pathogenic factor that contributes to these conditions is the persistent recruitment of leukocytes which are thought to contribute to the vascular and tissue injury. Although much work has focussed on the multitude of inflammatory mediators that contribute to leukocyte recruitment there is very little information regarding the role of endogenous anti-adhesive molecules that “turn off” the inflammatory response. Although nitric oxide, adenosine, prostacyclin and IL-10 have all been suggested to potentially play an important role as inhibitory regulators of adhesion, the focus of this review will be the role of nitric oxide as an anti-adhesive molecule. Areas of controversy and uncertainty will be highlighted and future directions will be identified.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Asako H, Kurose I, Wolf R, DeFrees S, Zheng Z, Phillips ML, Pauslon JC, Granger DN (1994) Role of HI receptors and P-selectin in histamine-induced leukocyte rolling and adhesion in postcapillary venules. J Clin Invest 93:1508–1515

    Article  PubMed  CAS  Google Scholar 

  2. Mayadas, TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD (1993) Leukocyte rolling and extravasation are severely compromised in P-selectin-deficient mice. Cell 74:541–554

    Article  PubMed  CAS  Google Scholar 

  3. Von Andrian UH, Chambers JD, McEvoy LM, Bargatze RF, Arfors KE, Butcher EC (1991) Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-l and the leukocyte β2 integrins in vivo. Proc Natl Acad Sci USA 88:7538–7542

    Article  Google Scholar 

  4. Wa1chek B, Moore KL, McEver RP, Kishomoto TK (1996) Neutrophil-neutrophil interactions under hydrodynamic shear stress involve L-selectin and PSGL-l.A mechanism that amplifies initial leukocyte accumulation on P-selectin in vitro. J Clin Invest 98:1081–1087

    Article  Google Scholar 

  5. Kishimoto TK, Anderson DC (I992) The role of integrins in inflammation. In Inflammation: Basic Principles and Clinical Correlates. Gallin JI, Goldstein IM, Snyderman R (eds) Raven Press, Ltd. NewYork:353–406

    Google Scholar 

  6. Alon R, Kassner PD, Carr MW, Finger EB, Hemler ME, Springer TA (1995) The integrin VLA-4supports tethering and rolling in flow on VCAM-I. J Cell Biol 128:1243–1253

    Article  PubMed  CAS  Google Scholar 

  7. Johnston B, Issekutz TB, Kubes P (1996) The α4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo. J Exp Med 181:1995–2006

    Article  Google Scholar 

  8. Granger DN, Kubes P (1994) The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukocyte Bioi 55:662–675

    CAS  Google Scholar 

  9. Wong J, Johnston B, Lee SS, Bullard DC, Smith CW, Beaudet AL, Kubes P (1997) A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest 99:2782–2790

    Article  PubMed  CAS  Google Scholar 

  10. Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  PubMed  CAS  Google Scholar 

  11. Kubes P, Suzuki M, Granger DN (1991) Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 88:4651–4655

    Article  PubMed  CAS  Google Scholar 

  12. Kubes P, Granger DN (1992) Nitric oxide modulates microvascular permeability. Am J Physiol 262:H611–H615

    PubMed  CAS  Google Scholar 

  13. Kurose I, Kubes P, Wolf R, Anderson DC, Paulson J, Miyasaka M, Granger DN (1993) Inhibition of nitric oxide production: Mechanisms of vascular albumin leakage. Circ Res 73:164–171

    Article  PubMed  CAS  Google Scholar 

  14. Nishida J, McCuskey RS, McDonnell D, Fox ES (1994) Protective role of nitric oxide in hepatic microcirculatory dysfunction during endotoxemia. Am J Physiol 267:G1135–G1141

    PubMed  CAS  Google Scholar 

  15. May GR, Crook P, Moore PK, Page CP (1991) The role of nitric oxide as an endogenous regulator of platelet and neutrophil activation within the pulmonary circulation of the rabbit. Br J Pharmacol 102:759–763

    Article  PubMed  CAS  Google Scholar 

  16. Ma S, Weyrich AS, Lefer DJ, Lefer AM (1993) Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to coronary endo-thelium. Circ Res 72:403–412

    Article  PubMed  CAS  Google Scholar 

  17. Kubes PS, Kanwar S, Niu X-F, Gaboury J (1993) Nitric oxide synthesis inhibition induces leukocyte adhesion via Superoxide and mast cells. FASEB J 7:1293–1299

    PubMed  CAS  Google Scholar 

  18. Suematsu M, Tamatani T, Delano FA, Miyasaka M, Forrest M, Suzuki H, Schmid-Schönbein GW (1994) Microvascular oxidative stress preceding leukocyte activation elicited by in vivo nitric oxide suppression. Am J Physiol 266:H2410–H2415

    PubMed  CAS  Google Scholar 

  19. Arndt H, Russell JM, Kurose I, Kubes P, Granger DN (1993) Mediators of leukocyte adhesion in rat mesenteric venules elicited by inhibition of nitric oxide synthesis. Gastroenterology 105:675–680

    PubMed  CAS  Google Scholar 

  20. Davenpeck KL, Gauthier TW, Lefer AM (1994) Inhibition of endothelial-derived nitric oxide promotes P-selectin expression and actions in the rat microcirculation. Gastroenterology 107:1050–1058

    PubMed  CAS  Google Scholar 

  21. Armstead VE, Minchenko AG, Schuhl RA, Hayward R, Nossuli TO, Lefer AM (1997) Regulation of P-selectin expression in human endothelial cells by nitric oxide. Am J Physiol 273:H740–H746

    PubMed  CAS  Google Scholar 

  22. Kanwar S, Wallace JL, Befus D, Kubes P (1994) Nitric oxide synthesis inhibition increasesepithelial permeability via mast cells. Am J Physiol 266:G222–G229

    PubMed  CAS  Google Scholar 

  23. Niu X-F, Smith CW, Kubes P (1994) Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils. Circ Res 74:1133–1140

    Article  PubMed  CAS  Google Scholar 

  24. Niu X-F, Ibbotson G, Kubes P (1996) A balance between nitric oxide and oxidants regulates mast cell-dependent neutrophil-endothelial cell interactions. Circ Res 79:992–999

    Article  PubMed  CAS  Google Scholar 

  25. Kurose I, Wolf R, Grisham MB, Aw TY, Specian RD, Granger DN (1995) Microvascular responses to inhibition of nitric oxide production: role of active oxidants. Circ Res 76:30–39

    Article  PubMed  CAS  Google Scholar 

  26. Cross CE (1987) Oxygen radicals and human disease. Ann Int Med 107:526–545

    PubMed  CAS  Google Scholar 

  27. Gaboury J, Woodman RC, Granger DN, Reinhardt P, Kubes P (1993) Nitric oxide prevents leukocyte adherence: role of Superoxide. Am J Physiol 265:H862–H867

    PubMed  CAS  Google Scholar 

  28. Johnston B, Kanwar S, Kubes P (1996) Hydrogen peroxide induces leukocyte rolling: modulation by endogenous antioxidant mechanisms including nitric oxide. Am J Physiol 40:614–621

    Google Scholar 

  29. Kubes P, Kanwar S (1994) Histamine induces leukocyte rolling in post-capillary venules: A P-selectin-mediated event. J Immunol 152:3570–3577

    PubMed  CAS  Google Scholar 

  30. Zimmerman GA, Prescott SM, Mclntyre TM (1992) Endothelial cell interactions with granulocytes: tethering and signaling molecules. Immunology Today 13:93–99

    Article  PubMed  CAS  Google Scholar 

  31. Salvemini D, Masini E, Pistelli A, Mannaioni PF, Vane J (1991) Nitric oxide: A regulatory mediator of mast cell rectivity. J Cardiovasc Pharmacol 17(suppl 3):S258–S264

    Article  CAS  Google Scholar 

  32. Hogaboam CM, Befus AD, Wallace JL (1993) Modulation of rat mast cell reactivity by IL-1 beta. Divergent effects on nitric oxide and platelet-activating factor release. J Immunol 151:3767–3774

    PubMed  CAS  Google Scholar 

  33. Gaboury JP, Niu XF, Kubes P (1996) Nitric oxide inhibits numerous features of mast cellinduced inflammation. Circulation 93:318–326

    Article  PubMed  CAS  Google Scholar 

  34. Gaboury JP, Johnston B, Niu XF, Kubes P (1995) Mechanism underlying acute mast cellinduced leukocyte rolling and adhesion in vivo. J Immunol 154:804–813

    PubMed  CAS  Google Scholar 

  35. Gauthier TW, Davenpeck KL, Lefer AM (1994) Nitric oxide attenuates leukocyte-endothelial interaction via P-selectin in splanchnic ischemia-reperfusion. Am J Physiol 267:G562–G568

    PubMed  CAS  Google Scholar 

  36. Kubes P, Kurose I, Granger DN (1994) NO donors prevent integrin-induced leukocyte adhesion, but not P-selectin-dependent rolling in postischemic venules. Am J Physiol 267:H931–H937

    PubMed  CAS  Google Scholar 

  37. Tsao PS, Aoki N, Lefer DJ, Johnson G, Lefer AM (1990) Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. Circulation 82:1402–1412

    Article  PubMed  CAS  Google Scholar 

  38. Kurose I, Wolf R, Grisham MB, Granger DN (1994) Modulation of ischemia/reperfusion-induced microvascular dysfunction by nitric oxide. Circ Res 74:376–382

    Article  PubMed  CAS  Google Scholar 

  39. Kanwar S, Tepperman BL, Payne D, Sutherland LR, Kubes P (1994) Time course of nitric oxide production and epithelial dysfunction during ischemia/reperfusion of the feline small intestine. Circ Shock 42:135–140

    PubMed  CAS  Google Scholar 

  40. Liu SF, Adcock IM, Old RW, Barnes PJ, Evans TW (1996) Differential regulation of the constitutive and inducible nitric oxide synthase mRNA by lipopolysaccharide treatment in vivo in the rat. Crit Care Med 24:1219–1225

    Article  PubMed  CAS  Google Scholar 

  41. Hutcheson IR, Whittle BJR, Boughton-Smith NK (1990) Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat. Br J Pharmacol 101:815–820

    Article  PubMed  CAS  Google Scholar 

  42. Boughton-Smith NK, Evans SM, Laszlo F, Whittle BJR, Moncada S (1993) The induction of nitric oxide synthase and intestinal vascular permeability endotoxin in the rat. Br J Pharmacol 110:1189–1195

    Article  PubMed  CAS  Google Scholar 

  43. Billiar TR, Curran RD, Harbrecht BG, Stuehr DJ, Demetris AJ, Simmons RL (1990) Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrite-nitrate biosynthesis while promoting hepatic damage. J Leukocyte Biol 48:565–569

    PubMed  CAS  Google Scholar 

  44. Tiao G, Rafferty J, Ogle C, Fischer JE, Hasseigren PO (1994) Detrimental effect of nitric oxide synthase inhibition during endotoxemia may be caused by high levels of tumor necrosis factor and interleukin-6. Surgery 116:332–338

    PubMed  CAS  Google Scholar 

  45. Harbrecht BG, Billiar TR, Stadler J, Demetris AJ, Ochoa J, Curran RD, Simmons RL (1992) Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury. J Leukocyte Biol 52:390–394

    PubMed  CAS  Google Scholar 

  46. Mulder MF, Van Lambalgen AA, Huisman E, Visser JJ, Van den Bos GC, Thijs LG (1994) Protective role of NO in the regional hemodynamic changes during acute endotoxemia in rats. Am J Physiol 266:H1558–H1564

    PubMed  CAS  Google Scholar 

  47. Lingnau W, McGuire R, Dehring DJ, Traber LD, Linares HA, Nelson SH, Kilbourn RG, Traber DL (1996) Changes in regional hemodynamics after nitric oxide inhibition during ovine bacteremia. Am J Physiol 270:R207–216

    PubMed  CAS  Google Scholar 

  48. Yan Z, Yokota T, Zhang W, Hansson GK (1996) Expression of inducible nitric oxide synthase inhibits platelet adhesion and restores blood flow in the injured artery. Circ Res 79:38–44

    Article  PubMed  CAS  Google Scholar 

  49. Hickey MJ, Sharkey KA, Sihota EG, Reinhardt PH, McMicking JD, Nathan C, Kubes P (1997) Inducible nitric oxide synthase-deficient mice have enhanced leukocyte-endothelium interactions in endotoxemia. FASEB J 11:955–964

    PubMed  CAS  Google Scholar 

  50. Cartwright JE, Johnstone AP, Whitley GSJ (1997) Inhibition of nitric oxide synthase by anti-sense techniques: investigations of the role of NO produced by murine macrophages. Br J Pharmacol 120:146–152

    Article  PubMed  CAS  Google Scholar 

  51. King JM, Srivastava KD, Stefano GB, Bilfinger TV, Bahou WF, Magazine HI (1997) Human monocyte adhesion is modulated by endothelin B receptor-coupled nitric oxide release. J Immunol 158:880–886

    PubMed  CAS  Google Scholar 

  52. Malmros C, Blomquist S, Dahm P, Martensson L, Thorne J (1996) Nitric oxide inhalation decreases pulmonary platelet and neutrophil sequestration during extracorporeal circulation in the pig. Crit Care Med 24:845–849

    Article  PubMed  CAS  Google Scholar 

  53. Bloomfield GL, Sweeney LB, Fischer BJ, Blocher CR, Sholley MM, Sugerman JH, Fowler AA III (1997) Delayed administration of inhaled nitric oxide preserves alveolar-capillary membrane integrity in porcine gram-negative sepsis. Arch Surg 132:65–75

    Article  PubMed  CAS  Google Scholar 

  54. Barbotin-Larrieu F, Mazmanian M, Baudet B, Detruit D, Chapelier A, Libert JM, Dartevelle P, Herve P (1996) Prevention of ischemia-reperfusion lung injury by inhaled nitric oxide in neonatal piglets. J Appl Physiol 80:782–788

    PubMed  CAS  Google Scholar 

  55. Guidot DM, Hybertson BM, Kitlowski RP, Repine JE (1996) Inhaled NO prevents IL-1-induced neutrophil accumulation and associated acute edema in isolated rat lungs. Am J Physiol 271:L225–229

    PubMed  CAS  Google Scholar 

  56. Fujino S, Nagahiro I, Trianafillou AN, Boasquevisque CH, Yano M, Cooper JD, Patterson GA (1997) Inhaled nitric oxide at the time of harvest improves early lung allograft function. Ann Thorac Surg 63:1383–1389

    Article  PubMed  CAS  Google Scholar 

  57. Rosenberg AA, Kisnella JP, Abman SH (1995) Cerebral hemodynamics and distribution of left ventricular output during inhalation of nitric oxide. Crit Care Med 23:1391–1397

    Article  PubMed  CAS  Google Scholar 

  58. Adrie, C, Bloch KD, Moreno PR, Hurford WE, Guerrero JL, Holt R, Zapol WM, Gold HK, Semigran MJ (1996) Inhaled nitric oxide increases coronary artery patency after thrombolysis. Circulation 94:1919–1926

    Article  PubMed  CAS  Google Scholar 

  59. Samama, CM, Diaby M, Fellahi JL, Mdhafar A, Eyraud D, Arock M, Guillosson JJ, Coriat P, Rouby JJ (1995) Inhibition of platelet aggregation by inhaled nitric oxide in patients with acute respiratory distress syndrome. Anesthesiol 83:56–65

    Article  CAS  Google Scholar 

  60. Hogman M, Frostell C, Arnberg H, Sandhagen B, Hedenstierna G (1994) Prolonged bleeding time during nitric oxide inhalation in the rabbit. Acta Physiol Scand 151:125–129

    Article  PubMed  CAS  Google Scholar 

  61. Gries A, Bottiger BW, Dorsam J, Bauer H, Weimann J, Bode C, Martin E, Motsch J (1997) Inhaled nitric oxide inhibits platelet aggregation after pulmonary embolism in pigs. Anesthesiol 86:387–393

    Article  CAS  Google Scholar 

  62. Gessler P, Nebe T, Birle A, Mueller W, Kachel W (1996) A new side effect of inhaled nitric oxide in neonates and infants with pulmonary hypertension: functional impairment of the neutrophil respiratory burst. Intensive Care Med 22:252–258

    Article  PubMed  CAS  Google Scholar 

  63. Chollet-Martin S, Gatecel C, Kermareec N, Gougerot-Pocidalo M, Payen DM (1996) Alveolar neutrophil functions and cytokine levels in patients with the adult respiratory distress syndrome during nitric oxide inhalation. Am J Respir Crit Care Med 153:985–990

    PubMed  CAS  Google Scholar 

  64. Edwards AD (1995) The pharmacology of inhaled nitric oxide. Arch Dis Child Fetal Neon Ed 72:F127–130

    Article  CAS  Google Scholar 

  65. Stamler JS, Simon DI, Osborne JA, Mullins ME, Jaraki O, Singel DJ, Loscalzo J (1992) S-nitro-sylation of proteins by nitric oxide: synthesis and characterization of novel biologically active compounds. Proc Natl Acad Sci USA 98:444–448

    Article  Google Scholar 

  66. Keaney JF Jr, Simon DI, Stamler JS, Jaraki O, Scharfstein J, Vita JA, Loscalzo J (1993) NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties. J Clin Invest 91:1582–1589

    Article  PubMed  CAS  Google Scholar 

  67. Jia L, Bonaventura C, Bonaventura J, Stamler JS (1996) S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control. Nature 380:221–226

    Article  PubMed  CAS  Google Scholar 

  68. Siegfried MR, Erhardt J, Rider T, Ma X, Lefer AM (1992) Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion. J Pharm Exp Ther 260:668–675

    CAS  Google Scholar 

  69. Fukatsu K, Saito H, Fukushima R, Inoue T, Lin M, Inaba T, Muto T (1995) Detrimental effects of a nitric oxide synthase inhibitor (N-w-nitro-L-arginine-methyl-ester) in a murine sepsis model. Arch Surg 130:410–414

    Article  PubMed  CAS  Google Scholar 

  70. Avontuur JA, Bruining HA, Ince C (1995) Inhibition of nitric oxide synthesis causes myocardial ischemia in endotoxemic rats. Circ Res 76:418–425

    Article  PubMed  CAS  Google Scholar 

  71. Petros A, Lamb G, Leone A, Moncada S, Bennett D, Vallance P (1994) Effects of a nitric oxide synthase inhibitor in humans with septic shock. Cardiovas Res 28:34–39

    Article  CAS  Google Scholar 

  72. Watson CA, Rees DD, Grover R (1997) Experience with nitric oxide synthase inhibitors in patients with septic shock. Shock 7(Suppl 1):264(Abstr.)

    Google Scholar 

  73. Michelson AD, Benoit SE, Furman MI, Breckwoldt WL, Rohrer MJ, Barnard MR, Loscalzo J (1996) Effects of nitric oxide/EDRF on platelet surface glycoproteins. Am J Physiol 270:H1640–H1648

    PubMed  CAS  Google Scholar 

  74. Biffi WL, Moore EE, Moore FA, Barnett C (1996) Nitric oxide reduces endothelial expression of intercellular adhesion molecule (ICAM)-l. J Surg Res 63:328–332

    Article  Google Scholar 

  75. Ikeda M, Ikeda IL, Takahashi M, Shimada K, Monota S, Kano S (1996) Nitric oxide inhibits intercellular adhesion molecule-1 expression in rat mesangial cells. J Am Soc Nephrol 7:2213–2218

    PubMed  CAS  Google Scholar 

  76. De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, Shin WS, Liao JK (1995) Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 96:60–68

    Article  PubMed  Google Scholar 

  77. Khan B, Harrison DG, Olbrych MT, Alexander RW, Medford RM (1996) Nitric oxide regulates vascular cell adhesion molecule-1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 93:9114–9119

    Article  PubMed  CAS  Google Scholar 

  78. Tsao PS, Buitrago R, Chan JR, Cooke JP (1996) Fluid flow inhibits endothelial adhesiveness. Nitric oxide and transcriptional regulation of VCAM-1. Circulation 94:1682–1689

    CAS  Google Scholar 

  79. Miles AM, Bohle DS, Glassbrenner PA, Hansert B, Wink DA, Grisham MB (1996) Modulation of superoxide-dependent oxidation and hydroxylation reactions by nitric oxide. J Biol Chem 271:40–47

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. M. J. Hickey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Kubes
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Ludwig-Boltzmann-Institut für experimentelle und klinische Traumatologie, Donaueschingenstraße 13, 1200, Wien, Austria

    Günther Schlag  & Heinz Redl  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer-Verlag Berlin Heidelberg

About this paper

Cite this paper

Hickey, M.J., Kubes, P. (1999). Nitric Oxide and Leukocyte Adhesion: Experience with NO Inhibitors, NO Donors and iNOS-Deficient Mice. In: Schlag, G., Redl, H. (eds) Shock, Sepsis, and Organ Failure. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-58630-9_8

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-58630-9_8

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63672-1

  • Online ISBN: 978-3-642-58630-9

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation