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Influence of N-acetylcysteine treatment on endotoxin-induced microcirculatory disturbances

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Abstract

Objectives

To determine the influence of N-acetylcysteine (NAC) in a treatment model, its effects on endotoxin-induced leukocyte-endothelial cell adhesion, vascular leakage, and venular micro-hemodynamics in postcapillary venules of rat mesentery.

Design

Prospective, randomized, controlled, experimental study.

Setting

Animal research laboratory.

Subjects

40 male Wistar rats.

Interventions

The rats randomly received one of four treatments: infusion of saline (SAL) or Escherichia coli lipopolysaccharides (LPS) followed by treatment with saline (SAL) or NAC (150 mg · kg− body weight) 30 min after induction of endotoxemia.

Measurements and main results

Leukocyte adherence, red blood cell velocity, and vessel diameters in postcapillary venules of rat mesentery were evaluated every 30 min over a period of 120 min using in vivo videomicroscopy. Vascular permeability was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate was calculated from red cell velocity, and vessel diameter. NAC in rats without endotoxemia (SAL + NAC group) compared to the control group (SAL + SAL) did not change microcirculatory parameters in postcapillary venules of rat mesentery. In both LPS-treated groups (LPS + SAL and LPS + NAC), leukocyte adherence increased after just 30 min. NAC treatment prevented a further increase in leukocyte adherence and attenuated the extravasation of fluorescence-labeled albumin during endotoxemia. Venular diameters remained unchanged, while erythrocyte velocity decreased in the LPS + SAL group. This led to a lower venular wall shear rate in this group.

Conclusions

Treatment with NAC attenuates endotoxin-induced leukocyte adherence and macromole-cular leakage in postcapillary venules of rat mesentery, showing that NAC is also effective after the onset of endotoxemia.

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References

  1. Williams JH Jr, Patel SK, Hatakeyama D, Arian R, Guo K, Hickey TJ, Liao SY, Ulich TR (1993) Activated pulmonary vascular neutrophils as early mediators of endotox-in-induced lung inflammation. Am J Respir Cell Mol Biol 8:134–144

    PubMed  CAS  Google Scholar 

  2. Malmros C, Hoist E, Hansson L, Martensson L, Thorne J (1994) Dynamic accumulation of neutrophils in lungs and visceral organs during early abdominal sepsis in the pig. World J Surg 18: 811–816

    Article  PubMed  CAS  Google Scholar 

  3. Fujishima S, Aikawa N (1995) Neutrophil-mediated tissue injury and its modulation. Intensive Care Med 21: 277–285

    Article  PubMed  CAS  Google Scholar 

  4. Xu H, Gonzalo JA, St Pierre Y, Williams IR, Kupper TS, Cotran RS, Springer Ta, Gutierrez-Ramos JC (1994) Leukocytosis and resistance to septic shock in intercellular adhesion molecule 1-deficient mice. J Exp Med 180: 95–109

    Article  PubMed  CAS  Google Scholar 

  5. Gressier B, Cabanis A, Lebegue S, Brunet C, Dine T, Luyckx M, Cazin M, Cazin JC (1994) Decrease of hypochlorous acid and hydroxyl radical generated by stimulated human neutrophils: comparison in vitro of some thiol-containing drugs. Methods Find Exp Clin Pharmacol 16: 9–13

    PubMed  CAS  Google Scholar 

  6. Aruoma OI, Halliwell B, Hoey BM, Butler J (1989) The antioxidant action of N-acetylcysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide, and hypochlorous acid. Free Radic Biol Med 6: 593–597

    Article  PubMed  CAS  Google Scholar 

  7. Bernard GR, Lucht WD, Niedermeyer ME, Snapper JR, Ogletree ML, Brigham KL (1984) Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function. J Clin Invest 73: 1772–1784

    Article  PubMed  CAS  Google Scholar 

  8. Peristeris P, Clark BD, Gatti S, Faggioni R, Mantovani A, Mengozzi M, Orencole SF, Sironi M, Ghezzi P (1992) N-acetylcysteine and gluthathione as inhibitors of tumor necrosis factor production. Cell Immunol 140:390–399

    Article  PubMed  CAS  Google Scholar 

  9. Kurose I, Suematsu M, Miura S, Fukumura D, Sekizuka E, Nagata H, Oshio C, Tsuchiya M (1993) Oxyradical formation from leukocytes during endotoxin-induced microcirculatory disturbance in rat mesentery-attenuating effect of cetraxate. Toxicol Appl Pharmacol 120: 37–44

    Article  PubMed  CAS  Google Scholar 

  10. Suzuki M, Asako H, Kubes P (1991) Neutrophil-derived oxidants promote leukocyte adherence in postcapillary venules. Microvasc Res 42:125–138

    Article  PubMed  CAS  Google Scholar 

  11. Becker M, Menger MD, Lehr HA (1994) Heparin-released superoxide dismutase inhibits postischemic leukocyte adhesion to venular endothelium. Am J Physiol 267: H925-H930

    PubMed  CAS  Google Scholar 

  12. Schmidt H, Schmidt W, Müller T, Böhrer H, Gebhard MM, Martin E (1997) N-acetylcysteine attenuates endotoxin-induced leukocyte-endothelial cell adhesion and macromolecular leakage in vivo. Crit Care Med 25: 858–863

    Article  PubMed  CAS  Google Scholar 

  13. Spies CD, Reinhart K, Witt I, Meier-Hellmann A, Hannemann L, Bredle DL, Schaffartzik W (1994) Influence of N-acetylcysteine on indirect indicators of tissue oxygenation in septic shock patients: results from a prospective, randomized, double-blind study. Crit Care Med 22: 1738–1746

    Article  PubMed  CAS  Google Scholar 

  14. Zhang H, Spapen H, Nguyen DN, Rogiers P, Bakker J, Vincent JL (1995) Effects of N-acetyl-L-cysteine on regional blood flow during endotoxic shock. Eur Surg Res 27: 292–300

    Article  PubMed  CAS  Google Scholar 

  15. Horan PK, Melnicoff MJ, Jensen BD, Slezak SE (1990) Fluorescent cell labeling for in vivo and in vitro cell tracking. Methods Cell Biol 33: 469–190

    Article  PubMed  CAS  Google Scholar 

  16. House SD, Lipowsky HH (1987) Leukocyte-endothelium adherence: microhemo-dynamics in mesentery of the cat. Microvasc Res 34: 363–379

    Article  PubMed  CAS  Google Scholar 

  17. Harris NR, Russell JM, Granger DN (1994) Mediators of endotoxin-induced leukocyte adhesion in mesenteric postcapillary venules. Circ Shock 43:155–160

    PubMed  CAS  Google Scholar 

  18. Braughler JM (1982) Involvement of sulf-hydryl groups in the oxidative modulation of particulate lung guanylate cyclase by nitric oxide and N-methyl-N’-nitro-N-nitro-soguanidine. Biochem Pharmacol 31: 1239–1244

    Article  PubMed  CAS  Google Scholar 

  19. Koeppel TA, Lehmann TG, Thies JC, Gehrcke R, Gebhard MM, Herfarth C, Otto G, Post S (1996) Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation. Transplantation 61:1397–1402

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  21. Redl H, Nikolai A, Kneidinger R, Schlag G (1993) Endothelial and leukocyte activation in experimental polytrauma and sepsis. Behring Inst Mitt 82: 218–228

    Google Scholar 

  22. Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320: 365–376

    PubMed  CAS  Google Scholar 

  23. Kurose I, Anderson DC, Miyasaka M, Tamatani T, Paulson JC, Todd RF, Rusche JR, Granger DN (1994) Molecular determinants of reperfusion-induced leukocyte adhesion and vascular protein damage. Circ Res 74: 336–343

    PubMed  CAS  Google Scholar 

  24. Leff JA, Wilke CP, Hybertson BM, Shanley PF, Beehler CJ, Repine JE (1993) Postinsult treatment with N-acetyl-L-cysteine decreases IL-1-induced neutrophil influx and lung leak in rats. Am J Physiol 265: L501-L506

    PubMed  CAS  Google Scholar 

  25. 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

    PubMed  CAS  Google Scholar 

  26. Masini E, Di Bello MG, Pistelli A, Raspanti S, Gambassi F, Mugnai L, Lupini M, Mannaioni PF (1994) Generation of nitric oxide from nitrovasodilators modulates the release of histamine from mast cells. J Physiol Pharmacol 45: 41–53

    PubMed  Google Scholar 

  27. Edwards MJ, Heniford BT, Miller FN (1992) Mast cell degranulation inhibits IL-2-induced microvascular protein leakage. J Surg Res 52: 429–435

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, University of Heidelberg, Im Neuenheimer Feld 110, D-69120, Heidelberg, Germany

    W. Schmidt, A. Walther, E. Martin & H. Schmidt

  2. Department of Experimental Surgery, University of Heidelberg, D-69120, Heidelberg, Germany

    M. M. Gebhard

Authors
  1. W. Schmidt
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  2. A. Walther
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  3. E. Martin
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  4. H. Schmidt
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  5. M. M. Gebhard
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Corresponding author

Correspondence to W. Schmidt.

Additional information

Supported by an Institutional Research Fund of the Department of Anesthesiology, University of Heidelberg, Germany

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Schmidt, W., Walther, A., Martin, E. et al. Influence of N-acetylcysteine treatment on endotoxin-induced microcirculatory disturbances. Intensive Care Med 24, 967–972 (1998). https://doi.org/10.1007/s001340050697

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  • DOI: https://doi.org/10.1007/s001340050697

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