Advertisement
Shock/Sepsis/Trauma/Critical Care| Volume 167, ISSUE 2, e307-e313, May 15, 2011

Antioxidant Treatment Reverses Organ Failure in Rat Model of Sepsis: Role of Antioxidant Enzymes Imbalance, Neutrophil Infiltration, and Oxidative Stress

Published:September 10, 2009DOI:https://doi.org/10.1016/j.jss.2009.08.005

      Background

      Some of the postulated molecular mechanisms of sepsis progression are linked with the imbalance between reactive oxygen species (ROS) production and its degradation by cellular antioxidant pathways. Some studies have correlated plasma oxidative stress, inflammatory markers, and clinical markers of organ failure, but none performed this in a systematic way, determining in situ oxidative and inflammatory markers and correlating these with markers of organ failure.

      Materials and Methods

      Rats subjected to cecal ligation and puncture (CLP) were treated with basic support or antioxidants and killed 12 h after to determine thiobarbituric acid reactive species (as an index of oxidative damage), superoxide dismutase (SOD), catalase (CAT), and myeloperoxidase (MPO) (as an index of neutrophil infiltration) in the kidney and lung. In addition, protein content in bronchoalveolar lavage fluid (as an index of lung alveolo-capillary dysfunction) and plasma urea (as an index of kidney injury) were measured at the same time.

      Results

      In the CLP group, we found a positive correlation between thiobarbituric acid reactive species (TBARS) and markers of organ injury in lung and kidney. Oxidative damage is correlated with an increase in SOD/CAT ratio only in the lung. In contrast, oxidative damage is correlated with MPO activity in the kidney, but not lung, suggesting different sources of oxidative damage depending on the analyzed organ. These reflect differences on the effects of basic support and antioxidants on organ dysfunction after sepsis.

      Conclusion

      Despite the general occurrence of oxidative damage in different organs during sepsis development and a positive correlation between oxidative markers and organ injury, antioxidant effects seemed to depend not only on the diminution of oxidative damage but also on its anti-inflammatory activity.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Journal of Surgical Research
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Angus D.C.
        • Linde-Zwirble W.T.
        • Lidicker J.
        • et al.
        Epidemiology of severe sepsis in the United States: Analysis of incidence, outcome, and associated costs of care.
        Crit Care Med. 2001; 29: 1303
        • Schrier R.W.
        • Wang W.
        Acute renal failure and sepsis.
        N Engl J Med. 2004; 351: 159
        • Hotchkiss R.S.
        • Karl I.E.
        The pathophysiology and treatment of sepsis.
        New Eng J Med. 2003; 348: 138
        • Salvemini D.
        • Cuzzocrea S.
        Oxidative stress in septic shock and disseminated intravascular coagulation.
        Free Radic Biol Med. 2002; 33: 1173
        • Winterbourn C.C.
        • Buss I.H.
        • Chan T.P.
        • et al.
        Protein carbonyl measurements show evidence of early oxidative stress in critically ill patients.
        Crit Care Med. 2000; 28: 143
        • Macarthur H.
        • Westfall T.C.
        • Riley D.P.
        • et al.
        Inactivation of catecholamines by superoxide gives new insights on the pathogenesis of septic shock.
        Proc Natl Acad Sci USA. 2000; 97: 9753
        • Andrades M.E.
        • Ritter C.
        • Dal-Pizzol F.
        The role of free radicals in sepsis development.
        Front Biosci. 2009; 1: 277
        • Barichello T.
        • Fortunato J.J.
        • Vitali A.M.
        • et al.
        Oxidative variables in the rat brain after sepsis induced by cecal ligation and perforation.
        Crit Care Med. 2006; 34: 886
        • Ritter C.
        • Andrades M.E.
        • Reinke A.
        • et al.
        Treatment with N-acetylcysteine plus deferoxamine protects rats against oxidative stress and improves survival in sepsis.
        Crit Care Med. 2004; 32: 342
        • Ritter C.
        • Andrades M.
        • Frota Junior M.L.
        • et al.
        Oxidative parameters and mortality in sepsis induced by cecal ligation and perforation.
        Intensive Care Med. 2003; 29: 1782
        • Andrades M.
        • Ritter C.
        • Moreira J.C.
        • Dal-Pizzol F.
        Oxidative parameters differences during non-lethal and lethal sepsis development.
        J Surg Res. 2005; 125: 68
        • Wichterman K.A.
        • Baue A.E.
        • Chaudry I.H.
        Sepsis and septic shock—a review of laboratory models and a proposal.
        J Surg Res. 1980; 29: 189
        • Hollenberg S.M.
        • Dumasius A.
        • Easington C.
        et al Characterization of a hyperdynamic murine model of resuscitated sepsis using echocardiography.
        Am J Respir Crit Care Med. 2001; 164: 891
        • Draper H.H.
        • Hadley M.
        Malondialdehyde determination as index of lipid peroxidation.
        Methods Enzymol. 1990; 186: 421
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • et al.
        Protein measurement with the Folin phenol reagent.
        J Biol Chem. 1951; 193: 265
        • Aebi H.
        Catalase in vitro.
        Methods Enzymol. 1984; 105: 121
        • Bannister J.V.
        • Calabrese L.
        Assays for superoxide dismutase.
        Methods Biochem Anal. 1987; 32: 279
        • Flohe L.
        • Günzler W.A.
        Assays of glutathione peroxidase.
        Methods Enzymol. 1984; 105: 114
        • De Young L.M.
        • Kheifets J.B.
        • Ballaron S.J.
        • et al.
        Edema and cell infiltration in the phorbol ester-treated mouse ear are temporally separate and can be differentially modulated by pharmacologic agents.
        Agents Actions. 1989; 26: 335
        • Ritter C.
        • da Cunha A.A.
        • Echer I.C.
        • et al.
        Effects of N-acetylcysteine plus deferoxamine in lipopolysaccharide induced acute lung injury in the rat.
        Crit Care Med. 2006; 34: 471
        • Buras J.A.
        • Holzmann B.
        • Sitkovsky M.
        Animal models of sepsis: Setting the stage.
        Nat Rev Drug Discov. 2005; 4: 854
        • Hubbard W.J.
        • Choudhry M.
        • Schwacha M.G.
        • et al.
        Cecal ligation and puncture.
        Shock. 2005; 52
        • Abraham E.
        • Singer M.
        Mechanism of sepsis-induced organ dysfunction.
        Crit Care Med. 2007; 35: 2408
        • Gras-Le Guen C.
        • Jarry A.
        • Vallette G.
        • et al.
        Antibiotic therapy reduces nitrosative stress and programmed cell death in the rabbit fetal lung.
        Eur Respir J. 2005; 25: 88
        • Durant R.
        • Klouche K.
        • Delbosc S.
        • et al.
        Superoxide anion overproduction in sepsis: Effects of vitamin e and simvastatin.
        Shock. 2004; 22: 34
        • Javesghani D.
        • Magder S.A.
        • Barreiro E.
        • et al.
        Molecular characterization of a superoxide-generating NAD(P)H oxidase in the ventilatory muscles.
        Am J Respir Crit Care Med. 2002; 165: 412
        • Luchtemberg M.N.
        • Petronilho F.
        • Constantino L.
        • et al.
        Xanthine oxidase activity in patients with sepsis.
        Clin Biochem. 2008; 41: 1186
        • Halliwell B.
        • Gutteridge J.M.
        Free radical in biology and medicine.
        Oxford University Press, Oxford, UK1999
        • Fullerton H.J.
        • Ditelberg J.S.
        • Chen S.F.
        • et al.
        Copper/zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia ischemia.
        Ann Neurol. 1998; 44: 357
        • Kelner M.J.
        • Bagnell R.
        • Montoya M.
        • et al.
        Transfection with human copper-zinc superoxide dismutase induces bidirectional alterations in other antioxidant enzymes, proteins, growth factor response, and paraquat resistance.
        Free Radic Biol Med. 1995; 18: 497
        • Omar B.A.
        • McCord J.M.
        The cardioprotective effect of Mn-superoxide dismutase is lost at high doses in the postischemic isolated rabbit heart.
        Free Radic Biol Med. 1990; 9: 473
        • Omar B.A.
        • Gad N.M.
        • Jordan M.C.
        • et al.
        Cardioprotection by CuZn-superoxide dismutase is lost at high doses in the reoxygenated heart.
        Free Radic Biol Med. 1990; 9: 465
        • Ebong S.
        • Call D.
        • Nemzek J.
        • Bolgos G.
        • et al.
        Immunopathologic alterations in murine models of sepsis of increasing severity.
        Infect Immun. 1999; 67: 6603
        • Visner G.A.
        • Dougall W.C.
        • Wilson J.M.
        • et al.
        Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1, and tumor necrosis factor. Role in the acute inflammatory response.
        J Biol Chem. 1990; 265: 2856
        • Dougall W.C.
        • Nick H.S.
        Manganese superoxide dismutase: A hepatic acute phase protein regulated by interleukin-6 and glucocorticoids.
        Endocrinology. 1991; 129: 2376
        • Kono Y.
        • Fridovich I.
        Superoxide radical inhibits catalase.
        J Biol Chem. 1982; 257: 5751
        • de Souza L.F.
        • Ritter C.
        • et al.
        Mitochondrial superoxide production is related to the control of cytokine release from peritoneal macrophage after antioxidant treatment in septic rats.
        J Surg Res. 2007; 141: 252
        • Hsu D.Z.
        • Su S.B.
        • Chien S.P.
        • et al.
        Effect of sesame oil on oxidative-stress-associated renal injury in endotoxemic rats: Involvement of nitric oxide and proinflammatory cytokines.
        Shock. 2005; 24: 276