Abstract
Endotoxemia in patients can lead to sepsis and shock by activation of cellular and plasmatic systems. Corticosteroids are described to have a beneficial effect on these phenomena. In this study of controlled endotoxic shock, we investigated the protective effects of prophylactic corticosteroid treatment against activation of cellular and plasmatic systems. In this respect, a low-dose methylprednisolone (1 mg/kg body wt) treatment was compared with that of a high-dose methylprednisolone (40 mg/kg body wt) treatment. Endotoxin infusion induced death of all rabbits, which was associated with leukopenia, thrombopenia, increased levels ofβ-glucuronidase, and leukotriene B4 (LTB4) and decreased levels of complement total hemolytic activity (CH50) and tissue plasminogen activator (t-PA) activity. Both methylprednisolone regimens prevented death of the rabbits after endotoxin infusion, which correlated with a significant decrease of the granulocyte release productβ-glucuronidase (P < 0.01). The early leukopenia and thrombopenia were not prevented; however, both cell numbers returned more rapidly to baseline values than in the placebo group (P < 0.01,P < 0.05). The LTB4 and CH50 concentration and t-PA activity did not differ significantly between the treated and placebo groups. These results indicate that although methylprednisolone has no inhibitory effect on the activation of the complement, arachidonic acid, and fibrinolytic systems, it protected the animals from the deleterious effects of endotoxin shock by inhibition of leukocyte activation. In this regard a low dosage of methylprednisolone is equally effective as the most often recommended high dose.
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Hammerschmidt, D.E., L.J. Weaver, L.D. Hudson, P.R. Craddock, andH.S. Jacob. 1980. Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome.Lancet 2:947–949.
Hinshaw, L.B. 1983. Overview of endotoxin shock.In Pathophysiology of Shock, Anoxia and Ischemia. R.A. Cowley and B.V. Trump, editors. Williams and Wilkins, Baltimore. 219–235.
Henson, P.M., andR.B. Johnston. 1987. Tissue injury in inflammation.J. Clin. Invest. 79:669–674.
Craddock, P.R., D.E. Hammerschmidt, J.G. White, A.P. Dalmasso, andH.S. Jacob. 1977. Complement (C5a)-induced granulocyte aggregation in vitro.J. Clin. Invest. 60:260–264.
Hoover, R.L., M.J. Karnovsky, K.F. Austen, E.J. Corey, andR.A. Lewis. 1984. Leukotriene B4 action on endothelium mediates augmented neutrophil endothelial adhesion.Proc. Natl. Acad. Sci. U.S.A. 81:2191–2193.
Colucci, M., J.A. Paramo, andD. Collen. 1985. Generation in plasma of a fast-acting inhibitor of plasminogen activator in response to endotoxin stimulation.J. Clin. Invest. 75:818–824.
Jansen, N.J.G., W. vanOeveren, B.Hoiting, and Ch.R.H.Wildevuur. Activation of plasmatic systems and blood cells by endotoxin in rabbits.Inflammation 15:81–90.
Boogaerts, M.A., C. Roelant, W. Goossens, andR.L. Verwilghen. 1986. Complement activation and adult respiratory distress syndrome during intermittent flow apheresis procedures.Transfusion 26:82–87.
Hinshaw, L.B., L.T. Archer, B.K. Beller-Todd, B. Benjamin, D.J. Flournoy, andR. Passey. 1981. Survival of primates in lethal septic shock following delayed treatment with steroid.Circ. Shock 8:291–300.
Weiler, J.M., andB.D. Packard. 1982. Methylprednisolone inhibits the alternative and amplification pathways of complement.Infect. Immun. 38:122–126.
Imai, T., T. Sato, andT. Fujita. 1982. Inhibitory effect of glucocorticoid on complement activation induced by lipopolysaccharide.Circ. Shock 9:55–62.
Fuller, R.W., C.R. Kelsey, P.J. Cole, C.T. Dollery, andJ. MacDermot. 1984. Dexamethasone inhibits the production of thromboxane B2 and leukotriene B4 by human alveolar and peritoneal macrophages in culture.Clin. Sci. 67:653–656.
Skubitz, K.M., andD.E. Hammerschmidt. 1986. Corticosteroids reversibly inhibit chemotactic peptide receptor binding and granulocyte response, yet allow desensitization and receptor down-regulation.Blood 68:830–836.
Jansen, N.J.G., W. van Oeveren, M.D. Kazatchkine, andCh.R.H. Wildevuur. 1989. Methylprednisolone does not inhibit granulocytopenia induced by complement-activated autologous plasma in rabbits.Biomaterials 10:617–621.
Sprung, C.L., P.V. Caralis, E.H. Marcial, M. Pierce, M.A. Gelbard, W.M. Long, R.C. Duncan, M.D. Tendler, andM. Karpf. 1984. The effects of high-dose corticosteroids in patients with septic shock: A prospective, controlled study.N. Engl. J. Med. 311:1137–1143.
Bone, R.C., and the methylprednisolone severe sepsis study group. 1987. A controlled clinical trial of high-dose methylprednisolone in the treatment of severe sepsis and septic shock.N. Engl. J. Med. 317:653–658.
Veterans Administration systemic sepsis cooperative study group. 1987. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis.N. Engl. J. Med. 317:659–665.
Mayer, M.M. 1971. Complement and complement fixation.In Experimental Immunochemistry. E.A. Kabat, editor. Charles C. Thomas, Springfield, Illinois. 133–140.
Baehner, R.L. 1975. Subcellular distribution of niroblue tetrazolium reductase (NBT-R) in human polymorphonuclear leuocytes (PMN).J. Lab. Clin. Med. 86:785–792.
Hammerschmidt, D.E., J.G. White, P.R. Craddock, andH.S. Jacob. 1979. Corticosteroids inhibit complement-induced granulocyte aggregation: A possible mechanism for their efficacy in shock states.J. Clin. Invest. 63:798–803.
Jacob, H.S. 1980. Complement-induced vascular leukostasis: its role in tissue injury.Arch. Pathol. Lab. Med. 104:617–620.
Skubitz, K.M., P.R. Craddock, D.E. Hammerschmidt, andJ.T. August. 1981. Corticosteroids block binding of chemotactic peptide to its receptor on granulocytes and cause disaggregation of granulocyte aggregates in vitro.J. Clin. Invest. 68:13–20.
Levine, P.H., J.C. Hardin, K.L. Scoom, andN.I. Krinsky. 1981. Effect of corticosteroids on the production of superoxide and hydrogen peroxide and the appearance of chemiluminescence by phagocytosing polymorphonuclear leukocytes.Inflammation 5:19–27.
Bredenberg, C.E., G.A. Taylor, andW.R. Webb. 1980. The effect of thrombocytopenia on the pulmonary and systemic hemodynamics of canine endotoxin shock.Surgery 87:59–68.
Seeger, W., H. Wolf, andG. Stahler. 1982. Increased pulmonary vascular resistance and permeability due to arachidonate metabolism in isolated rabbit lungs.Prostaglandin 23:157–173.
Virella, G., M.F.L. Lopes-Virella, C. Schuler, T. Sherwood, G.A. Espinoza, P. Winocour, andJ.A. Colwell. 1983. Release of PAF by human polymorphonuclear leukocytes stimulated by immune complexes bound to sepharose particles and human erythrocytes.Immunology 50:43–51.
Brigham, K. 1985. Metabolites of arachidonic acid in experimental lung vascular injury.Fed. Proc. 44:43–45.
Lewis, R.A., andK.F. Austen. 1984. The biologically active leukotrienes: biosynthesis, metabolism and pharmacology.J. Clin. Invest. 73:889–897.
Emeis, J.J., andT. Kooistra. 1986. Interleukin-I and lipopolysaccharide induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells.J. Exp. Med. 163:1260–1266.
Cwikel, B.J., P.A. Barouski Miller, P.L. Colemann, andT.D. Gelehrter. 1984. Dexamethasone induction of an inhibitor of plasminogen activator in HTC hepatoma cells.J. Biol. Chem. 259:6847–6851.
Crutchley, D.J., L.B. Conanan, andJ.R. Maynard. 1981. Human fibroblasts produce inhibitor directed against plasminogen activator when treated with glucocorticoids.Ann. N. Y. Acad. Sci. 370:609–616.
Beutler, B., N. Krochin, I.W. Milsark, C. Luedke, andA. Cerami. 1986. Control of cachectin (tumor necrosis factor) synthesis: Mechanism of endotoxin resistance.Science 232:977–980.
Beutler, B., andA. Cerami. 1986. Cachectin and tumor necrosis factor as two sides of the same biological coin.Nature 320:584–588.
Hoyoux, C., J. Foidart, P. Rigo, P. Mahieu, andF. Geubelle. 1984. Effects of methylprednisolone on the Fc-receptor function of human reticulo-endothelial system in vivo.Eur. J. Clin. Invest. 14:60–66.
Weigelt, J.A., J.F. Norcross, K.R. Borman, andW.H. Snyder III. 1985. Early steroid therapy for respiratory failure.Arch. Surg. 120:536–540.
Meuleman, J., andP. Katz. 1985. The immunologic effects, kinetics, and use of glucocorticosteroids.Med. Clin. North Am. 69:805–816.
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Jansen, N.J.G., Van Oeveren, W., Hoiting, B.H. et al. Methylprednisolone prophylaxis protects against endotoxin-induced death in rabbits. Inflammation 15, 91–101 (1991). https://doi.org/10.1007/BF00917504
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DOI: https://doi.org/10.1007/BF00917504