Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1987 May;79(5):1498–1509. doi: 10.1172/JCI112980

Platelet-activating factor mediates hemodynamic changes and lung injury in endotoxin-treated rats.

S W Chang, C O Feddersen, P M Henson, N F Voelkel
PMCID: PMC424426  PMID: 3553241

Abstract

Within 20 min after intraperitoneal injection of Salmonella enteritidis endotoxin in rats, blood platelet-activating factor (PAF) increased from 4.3 +/- 1.3 to 13.7 +/- 2.0 ng/ml (P less than 0.01) and lung PAF from 32.3 +/- 4.9 to 312.3 +/- 19.6 ng (P less than 0.01), but not lung lavage PAF. We tested the effect of PAF receptor antagonists, CV 3988 and SRI 63-441, on endotoxin-induced hemodynamic changes and lung vascular injury. Pretreatment with CV 3988 attenuated systemic hypotension, preserved hypoxic pulmonary vasoconstriction, and prolonged survival of awake catheter-implanted endotoxin-treated (20 mg/kg) rats. Pretreatment with SRI 63-441 prevented the depressed hypoxic pulmonary vasoconstriction after low dose (2 mg/kg) endotoxin. Both CV 3988 and SRI 63-441 blocked the increased extravascular accumulation of 125I-albumin and water in perfused lungs isolated from endotoxin-treated rats. We conclude that PAF is produced in the lung during endotoxemia and may be an important mediator of the systemic and pulmonary hemodynamic changes as well as the acute lung vascular injury after endotoxemia.

Full text

PDF
1505

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adnot S., Lefort J., Lagente V., Braquet P., Vargaftig B. B. Interference of BN 52021, a PAF-acether antagonist, with endotoxin-induced hypotension in the guinea-pig. Pharmacol Res Commun. 1986 Aug;18 (Suppl):197–200. doi: 10.1016/0031-6989(86)90052-4. [DOI] [PubMed] [Google Scholar]
  2. BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
  3. Begley C. J., Ogletree M. L., Meyrick B. O., Brigham K. L. Modification of pulmonary responses to endotoxemia in awake sheep by steroidal and nonsteroidal anti-inflammatory agents. Am Rev Respir Dis. 1984 Dec;130(6):1140–1146. doi: 10.1164/arrd.1984.130.6.1140. [DOI] [PubMed] [Google Scholar]
  4. Benveniste J. Platelet-activating factor, a new mediator of anaphylaxis and immune complex deposition from rabbit and human basophils. Nature. 1974 Jun 7;249(457):581–582. doi: 10.1038/249581a0. [DOI] [PubMed] [Google Scholar]
  5. Bessin P., Bonnet J., Apffel D., Soulard C., Desgroux L., Pelas I., Benveniste J. Acute circulatory collapse caused by platelet-activating factor (PAF-acether) in dogs. Eur J Pharmacol. 1983 Jan 21;86(3-4):403–413. doi: 10.1016/0014-2999(83)90190-5. [DOI] [PubMed] [Google Scholar]
  6. Brigham K. L., Begley C. J., Bernard G. R., Hutchison A. A., Loyd J. E., Lucht W. D., Meyrick B., Newman J. H., Niedermeyer M. E., Ogletree M. L. Septicemia and lung injury. Clin Lab Med. 1983 Dec;3(4):719–744. [PubMed] [Google Scholar]
  7. Caillard C. G., Mondot S., Zundel J. L., Julou L. Hypotensive activity of PAF-acether in rats. Agents Actions. 1982 Dec;12(5-6):725–730. doi: 10.1007/BF01965093. [DOI] [PubMed] [Google Scholar]
  8. Camussi G., Aglietta M., Malavasi F., Tetta C., Piacibello W., Sanavio F., Bussolino F. The release of platelet-activating factor from human endothelial cells in culture. J Immunol. 1983 Nov;131(5):2397–2403. [PubMed] [Google Scholar]
  9. Camussi G., Pawlowski I., Bussolino F., Caldwell P. R., Brentjens J., Andres G. Release of platelet activating factor in rabbits with antibody-mediated injury of the lung: the role of leukocytes and of pulmonary endothelial cells. J Immunol. 1983 Oct;131(4):1802–1807. [PubMed] [Google Scholar]
  10. Chang J. C., Lesser M. Quantitation of leukocytes in bronchoalveolar lavage samples from rats after intravascular injection of endotoxin. Am Rev Respir Dis. 1984 Jan;129(1):72–75. doi: 10.1164/arrd.1984.129.1.72. [DOI] [PubMed] [Google Scholar]
  11. Chilton F. H., Ellis J. M., Olson S. C., Wykle R. L. 1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine. A common source of platelet-activating factor and arachidonate in human polymorphonuclear leukocytes. J Biol Chem. 1984 Oct 10;259(19):12014–12019. [PubMed] [Google Scholar]
  12. Cook J. A., Wise W. C., Halushka P. V. Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency. J Clin Invest. 1980 Jan;65(1):227–230. doi: 10.1172/JCI109655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cook J. A., Wise W. C., Halushka P. V. Protective effect of a selective leukotriene antagonist in endotoxemia in the rat. J Pharmacol Exp Ther. 1985 Nov;235(2):470–474. [PubMed] [Google Scholar]
  14. Dawson C. A., Linehan J. H., Rickaby D. A. Pulmonary microcirculatory hemodynamics. Ann N Y Acad Sci. 1982;384:90–106. doi: 10.1111/j.1749-6632.1982.tb21365.x. [DOI] [PubMed] [Google Scholar]
  15. Demling R. H., Smith M., Gunther R., Flynn J. T., Gee M. H. Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep. Am J Physiol. 1981 Mar;240(3):H348–H353. doi: 10.1152/ajpheart.1981.240.3.H348. [DOI] [PubMed] [Google Scholar]
  16. Doebber T. W., Wu M. S., Robbins J. C., Choy B. M., Chang M. N., Shen T. Y. Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone. Biochem Biophys Res Commun. 1985 Mar 29;127(3):799–808. doi: 10.1016/s0006-291x(85)80014-0. [DOI] [PubMed] [Google Scholar]
  17. Drake R., Gaar K. A., Taylor A. E. Estimation of the filtration coefficient of pulmonary exchange vessels. Am J Physiol. 1978 Mar;234(3):H266–H274. doi: 10.1152/ajpheart.1978.234.3.H266. [DOI] [PubMed] [Google Scholar]
  18. Grandel K. E., Farr R. S., Wanderer A. A., Eisenstadt T. C., Wasserman S. I. Association of platelet-activating factor with primary acquired cold urticaria. N Engl J Med. 1985 Aug 15;313(7):405–409. doi: 10.1056/NEJM198508153130702. [DOI] [PubMed] [Google Scholar]
  19. Hagmann W., Denzlinger C., Keppler D. Production of peptide leukotrienes in endotoxin shock. FEBS Lett. 1985 Jan 28;180(2):309–313. doi: 10.1016/0014-5793(85)81092-9. [DOI] [PubMed] [Google Scholar]
  20. Hales C. A., Sonne L., Peterson M., Kong D., Miller M., Watkins W. D. Role of thromboxane and prostacyclin in pulmonary vasomotor changes after endotoxin in dogs. J Clin Invest. 1981 Aug;68(2):497–505. doi: 10.1172/JCI110281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Handley D. A., Arbeeny C. M., Lee M. L., Van Valen R. G., Saunders R. N. Effect of platelet activating factor on endothelial permeability to plasma macromolecules. Immunopharmacology. 1984 Dec;8(3-4):137–142. doi: 10.1016/0162-3109(84)90017-1. [DOI] [PubMed] [Google Scholar]
  22. Handley D. A., Tomesch J. C., Saunders R. N. Inhibition of PAF-induced systemic responses in the rat, guinea pig, dog and primate by the receptor antagonist SRI 63-441. Thromb Haemost. 1986 Aug 20;56(1):40–44. [PubMed] [Google Scholar]
  23. Heffner J. E., Shoemaker S. A., Canham E. M., Patel M., McMurtry I. F., Morris H. G., Repine J. E. Acetyl glyceryl ether phosphorylcholine-stimulated human platelets cause pulmonary hypertension and edema in isolated rabbit lungs. Role of thromboxane A2. J Clin Invest. 1983 Feb;71(2):351–357. doi: 10.1172/JCI110776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Heflin A. C., Jr, Brigham K. L. Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest. 1981 Nov;68(5):1253–1260. doi: 10.1172/JCI110371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Henson P. M. Activation and desensitization of platelets by platelet-activating factor (PAF) derived from IgE-sensitized basophils. I. Characteristics of the secretory response. J Exp Med. 1976 Apr 1;143(4):937–952. doi: 10.1084/jem.143.4.937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Henson P. M., Larsen G. L., Webster R. O., Mitchell B. C., Goins A. J., Henson J. E. Pulmonary microvascular alterations and injury induced by complement fragments: synergistic effect of complement activation, neutrophil sequestration, and prostaglandins. Ann N Y Acad Sci. 1982;384:287–300. doi: 10.1111/j.1749-6632.1982.tb21379.x. [DOI] [PubMed] [Google Scholar]
  27. Huber F., Sodal I. E., Weil J. V. On-line cardiac output by digital computer. J Appl Physiol. 1976 Feb;40(2):266–268. doi: 10.1152/jappl.1976.40.2.266. [DOI] [PubMed] [Google Scholar]
  28. Hunninghake G. W., Gadek J. E., Kawanami O., Ferrans V. J., Crystal R. G. Inflammatory and immune processes in the human lung in health and disease: evaluation by bronchoalveolar lavage. Am J Pathol. 1979 Oct;97(1):149–206. [PMC free article] [PubMed] [Google Scholar]
  29. Hutchison A. A., Ogletree M. L., Snapper J. R., Brigham K. L. Effect of endotoxemia on hypoxic pulmonary vasoconstriction in unanesthetized sheep. J Appl Physiol (1985) 1985 May;58(5):1463–1468. doi: 10.1152/jappl.1985.58.5.1463. [DOI] [PubMed] [Google Scholar]
  30. Iñarrea P., Gomez-Cambronero J., Pascual J., Ponte M. C., Hernando L., Sánchez-Crespo M. Synthesis of PAF-acether and blood volume changes in gram-negative sepsis. Immunopharmacology. 1985 Feb;9(1):45–52. doi: 10.1016/0162-3109(85)90046-3. [DOI] [PubMed] [Google Scholar]
  31. Johnson K. J., Ward P. A. Acute immunologic pulmonary alveolitis. J Clin Invest. 1974 Aug;54(2):349–357. doi: 10.1172/JCI107770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Lambrecht G., Parnham M. J. Kadsurenone distinguishes between different platelet activating factor receptor subtypes on macrophages and polymorphonuclear leucocytes. Br J Pharmacol. 1986 Feb;87(2):287–289. doi: 10.1111/j.1476-5381.1986.tb10816.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Lefer A. M., Müller H. F., Smith J. B. Pathophysiological mechanisms of sudden death induced by platelet activating factor. Br J Pharmacol. 1984 Sep;83(1):125–130. doi: 10.1111/j.1476-5381.1984.tb10126.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lemanske R. F., Jr, Guthman D. A., Oertel H., Barr L., Kaliner M. The biologic activity of mast cell granules. VI. The effect of vinblastine-induced neutropenia on rat cutaneous late phase reactions. J Immunol. 1983 Jun;130(6):2837–2842. [PubMed] [Google Scholar]
  35. McMurtry I. F., Davidson A. B., Reeves J. T., Grover R. F. Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs. Circ Res. 1976 Feb;38(2):99–104. doi: 10.1161/01.res.38.2.99. [DOI] [PubMed] [Google Scholar]
  36. McMurtry I. F., Morris K. G. Platelet-activating factor causes pulmonary vasodilation in the rat. Am Rev Respir Dis. 1986 Oct;134(4):757–762. doi: 10.1164/arrd.1986.134.4.757. [DOI] [PubMed] [Google Scholar]
  37. Meyrick B., Brigham K. L. Acute effects of Escherichia coli endotoxin on the pulmonary microcirculation of anesthetized sheep structure:function relationships. Lab Invest. 1983 Apr;48(4):458–470. [PubMed] [Google Scholar]
  38. Mojarad M., Hamasaki Y., Said S. I. Platelet-activating factor increases pulmonary microvascular permeability and induces pulmonary edema. A preliminary report. Bull Eur Physiopathol Respir. 1983 May-Jun;19(3):253–256. [PubMed] [Google Scholar]
  39. Pirotzky E., Bidault J., Burtin C., Gubler M. C., Benveniste J. Release of platelet-activating factor, slow-reacting substance, and vasoactive amines from isolated rat kidneys. Kidney Int. 1984 Feb;25(2):404–410. doi: 10.1038/ki.1984.31. [DOI] [PubMed] [Google Scholar]
  40. Prevost M. C., Cariven C., Simon M. F., Chap H., Douste-Blazy L. Platelet activating factor (PAF-acether) is released into rat pulmonary alveolar fluid as a consequence of hypoxia. Biochem Biophys Res Commun. 1984 Feb 29;119(1):58–63. doi: 10.1016/0006-291x(84)91617-6. [DOI] [PubMed] [Google Scholar]
  41. Rinaldo J. E., Dauber J. H., Christman J., Rogers R. M. Neutrophil alveolitis following endotoxemia. Enhancement by previous exposure to hyperoxia. Am Rev Respir Dis. 1984 Dec;130(6):1065–1071. doi: 10.1164/arrd.1984.130.6.1065. [DOI] [PubMed] [Google Scholar]
  42. Shaw J. O., Pinckard R. N., Ferrigni K. S., McManus L. M., Hanahan D. J. Activation of human neutrophils with 1-O-hexadecyl/octadecyl-2-acetyl-sn-glycerol-3-phosphorylcholine (platelet activating factor). J Immunol. 1981 Sep;127(3):1250–1255. [PubMed] [Google Scholar]
  43. Stanbrook H. S., Morris K. G., McMurtry I. F. Prevention and reversal of hypoxic pulmonary hypertension by calcium antagonists. Am Rev Respir Dis. 1984 Jul;130(1):81–85. doi: 10.1164/arrd.1984.130.1.81. [DOI] [PubMed] [Google Scholar]
  44. Terashita Z., Imura Y., Nishikawa K. Inhibition by CV-3988 of the binding of [3H]-platelet activating factor (PAF) to the platelet. Biochem Pharmacol. 1985 May 1;34(9):1491–1495. doi: 10.1016/0006-2952(85)90689-6. [DOI] [PubMed] [Google Scholar]
  45. Terashita Z., Imura Y., Nishikawa K., Sumida S. Is platelet activating factor (PAF) a mediator of endotoxin shock? Eur J Pharmacol. 1985 Feb 26;109(2):257–261. doi: 10.1016/0014-2999(85)90427-3. [DOI] [PubMed] [Google Scholar]
  46. Terashita Z., Tsushima S., Yoshioka Y., Nomura H., Inada Y., Nishikawa K. CV-3988 - a specific antagonist of platelet activating factor (PAF). Life Sci. 1983 Apr 25;32(17):1975–1982. doi: 10.1016/0024-3205(83)90049-8. [DOI] [PubMed] [Google Scholar]
  47. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  48. Voelkel N. F., Chang S. W., Pfeffer K. D., Worthen S. G., McMurtry I. F., Henson P. M. PAF antagonists: different effects on platelets, neutrophils, guinea pig ileum and PAF-induced vasodilation in isolated rat lung. Prostaglandins. 1986 Sep;32(3):359–372. doi: 10.1016/0090-6980(86)90005-5. [DOI] [PubMed] [Google Scholar]
  49. Voelkel N. F. Species variations in the pulmonary responses to arachidonic acid metabolites. Prostaglandins. 1985 May;29(5):867–889. doi: 10.1016/0090-6980(85)90143-1. [DOI] [PubMed] [Google Scholar]
  50. Voelkel N. F., Worthen S., Reeves J. T., Henson P. M., Murphy R. C. Nonimmunological production of leukotrienes induced by platelet-activating factor. Science. 1982 Oct 15;218(4569):286–289. doi: 10.1126/science.7123233. [DOI] [PubMed] [Google Scholar]
  51. Weir E. K., Mlczoch J., Reeves J. T., Grover R. F. Endotoxin and prevention of hypoxic pulmonary vasoconstriction. J Lab Clin Med. 1976 Dec;88(6):975–983. [PubMed] [Google Scholar]
  52. Winn R., Harlan J., Nadir B., Harker L., Hildebrandt J. Thromboxane A2 mediates lung vasoconstriction but not permeability after endotoxin. J Clin Invest. 1983 Sep;72(3):911–918. doi: 10.1172/JCI111062. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES