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October 1992

Complement Activation and Polymorphonuclear Neutrophil Leukocyte Elastase in SepsisCorrelation With Severity of Disease

Author Affiliations

From the Institute of Emergency Surgery (Drs Padalino, Chiara, and Nespoli), the Clinical Medicine (Drs Gardinali, Calcagno, Conciato, and Agostoni), Intensive Care Unit San Paolo Hospital (Dr Vesconi), and the Department of Food Science and Microbiology (Mr Ciappellano), University of Milan (Italy).

Arch Surg. 1992;127(10):1219-1224. doi:10.1001/archsurg.1992.01420100077014

• Complement activation is necessary for an adequate immune and inflammatory response to infections. Activation releases anaphylatoxins that cause vasodilation, increase vascular permeability, and trigger release of polymorphonuclear neutrophil leukocyte (PMN) lysosomal enzyme and oxygen radicals. Under normal circumstances, an orderly progression of such events has a beneficial antimicrobial effect. The same mechanism, however, when uncontrolled, may damage host tissues. To provide information about the clinical importance of such events in sepsis, different complement parameters (C3, C4, and the desarginated forms of C3a [C3ades-Arg] and C5a [C5ades-Arg]), PMN elastase, and malondialdehyde (a by-product of membrane peroxidation by oxygen radicals) were measured daily in 26 septic patients and correlated with two objectively assessed and previously validated severity scores (acute physiology and chronic health evaluation [APACHE II] and Sepsis Severity Score [SSS]). Nonsurvivors (n=12) had significantly greater and longer lasting complement activation than that in survivors, as reflected by higher levels of catabolic peptides (C3ades-Arg) and lower levels of native proteins (C3 and C4). C3ades-Arg, C3, C4, and the C3ades-Arg-C3 ratio were correlated with Sepsis Severity Scores. Polymorphonuclear neutrophil leukocyte elastase levels were higher in nonsurvivors and were correlated with C3ades-Arg and the C3ades-Arg-C3 ratio. Malondialdehyde levels were significantly higher in all patients than in controls, without, however, any relationship to severity of disease or clinical outcome. Since the higher and more persistent the complement activation and polymorphonuclear neutrophil leukocyte stimulation, the worse the patient's prognosis, we conclude that these mechanisms may be important in the clinical development of sepsis.

(Arch Surg. 1992;127:1219-1224)

Knaus WA, Draper EA, Wagner DP, Zimmerman JE.  Prognosis in acute organ-system failure . Ann Surg . 1985;202:685-693.Article
Fry E, Pearlstein L, Fulton RL, Polk HC.  Multiple system organ failure: the role of uncontrolled infection . Arch Surg . 1980;115:136-140.Article
Carrico CJ, Meakins JL, Marshall JC, Fry D, Maier RV.  Multiple organ failure syndrome . Arch Surg . 1986;121:196-208.Article
Siegel JH, Cerra FB, Coleman B, et al.  Physiological and metabolic correlations in human sepsis . Surgery . 1979;86:163-193.
Cooper NR, Nemerow GR.  Complement and infectious agents: a tale of disguise and deception . Complement Inflamm . 1989;6:249-258.
Hugh TE.  Biochemistry and biology of anaphylatoxins . Complement Inflamm . 1986;3:111-127.
Taylor PW, Kroll HP.  Interaction of human complement proteins with serum-sensitive and serum-resistant strains of E coli . Mol Immunol . 1984;21: 609-620.Article
Joiner KA, Brown EJ, Frank MM.  Complement and bacteria: chemistry and biology in host defense . Annu Rev Immunol . 1984;2:461-491.Article
Lundberg C, Gardinali M, Marceau F, Hugli TE.  Effects of the anaphylatoxins on vascular tissue in vivo and in vitro . In: Ryan US, ed. Endothelial Cell . Boca Raton, Fla: CRC Press Inc; 1987;2:243-257.
Guthrie LA, McPhail LC, Henson PM, Johnston RB Jr.  Priming of neutrophils for enhanced release of oxygen metabolites by bacterial lipopolysaccharides . J Exp Med . 1984;160:1656-1671.Article
Okusawa S, Yancey KB, van der Meer JW, et al.  C5a stimulates secretion of TNF mononuclear cells in vitro: comparison with secretion of interleukin 1β and interleukin 1α . J Exp Med . 1988;168:443-448.Article
Okusawa S, Dinarello CA, Yancey KB, et al.  C5a induction of human interleukin, I: synergistic effect with endotoxins or interferon gamma . J Immunol . 1987;139:26-35.
Zimmerman GA, Renzetti AD, Hill HR.  Functional and metabolic activity of granulocytes from patients with adult respiratory distress syndrome . Am Rev Respir Dis . 1983;127:290-300.
Nelson RD, Chenoweth DE, Solem LD.  Cytotaxin receptors on human neutrophils: modulation of C5a and peptide receptor number . Agents Actions . 1983;12:274-289.
Stevens JH, O'Hanley P, Shapiro JM, et al.  Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates . J Clin Invest . 1986;77:1812-1816.Article
Smedegard G, Cui L, Hugli TE.  Endotoxin-induced shock in the rat: a role for C5a . Am J Pathol . 1989;135:489-497.
Schirmer WJ, Schirmer JM, Naff GB, Fry DE.  Systemic complement activation produces hemodynamic changes characteristic of sepsis . Arch Surg . 1988;123:316-321.Article
McCabe WR.  Serum complement levels in bacteremia due to gram-negative organism . N Engl J Med . 1973;288:21-23.Article
Fearon DT, Ruddy S, Schur PH, McCabe WR.  Activation of the properdin pathway of complement in patients with gram-negative bacteremia . N Engl J Med . 1975;292:937-940.Article
Bengtson A, Heideman M.  Anaphylatoxin formation in sepsis . Arch Surg . 1988;123:645-649.Article
Weinberg PF, Matthay MA, Webster RO, Roskos KV, Goldstein IM, Murray JF.  Biologically active products of complement and acute lung injury in patients with the sepsis syndrome . Am Rev Respir Dis . 1984;130:791-796.
Heideman M, Norder-Hansson B, Mollnes TE.  Terminal complement complexes and anaphylatoxins in septic and ischemic patients . Arch Surg . 1988;123:188-192.Article
Hack CE, Nuijens JH, Felt-Bersma RJF, et al.  Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis . Am J Med . 1989;86:20-26.Article
Nuijens JH, Eerenberg-Belmer AJM, Huijbregts CCM, et al.  Proteolytic inactivation of plasma C1 inhibitor in sepsis . J Clin Invest . 1989;84:443-450.Article
Padalino P, Gardinali M, Pallavicini J, Chiara O, Bisiani G, Nespoli A.  Complement activation and endotoxin in sepsis . In: Schlag G, Redl A, eds. Second Vienna Shock Forum . New York, NY: Alan R Liss Inc; 1989;277-282.
Stevens LE.  Gauging the severity of surgical sepsis . Arch Surg . 1983; 118:1190-1192.Article
Knaus WA, Draper EA, Wagner DP, Zimmerman JE.  APACHE II: a severity of disease classification system . Crit Care Med . 1985;13:818-828.Article
Neumann S, Hennrich N, Gunzer G, Lang H.  Enzyme linked immunoassay for human granulocyte elastase in complex with α1-proteinase inhibitor . In: Horl W, Heidland A, eds. Proteases: Potential Role in Health and Diseases . New York, NY: Plenum Press; 1984:379-390.
Duswald KH, Jochum M, Schramm W, Fritz H.  Released granulocytic elastase: an indicator of pathobiochemical alterations in septicemia after abdominal surgery . Surgery . 1985;98:892-899.
Marx JL.  Oxygen free radicals linked to many diseases . Science . 1987;235:529-531.Article
Belmont HM, Hopkins P, Edelson HS, et al.  Complement activation during systemic lupus erythematosus: C3a and C5a anaphylatoxins circulate during exacerbations of disease . Arthritis Rheum . 1986;29:1085-1089.Article
O'Flaherty JT, Craddock PR, Jacob HS.  Mechanism of anti-complementary activity of corticosteroids in vivo: possible relevance in endotoxin shock . Proc Soc Exp Biol Med . 1977;154:206-209.Article
Hugli TE, Chenoweth DE.  Biologically active peptides of complement: techniques and significance of C3a and C5a measurements . In: Nakamura RM, Dito WR, Tucker ES III, eds. Immunoassays: Clinical Laboratory Techniques for the 1980s . New York, NY: Alan R Liss Inc; 1981;4:443-460.
Hoshino N, Nakajima R, Yamazaki I.  The effect of polymerization of horseradish peroxidase on the peroxidase activity in the presence of excess H2O2: a background for a homogeneous enzyme immunoassay . J Biochem (Tokyo) . 1987;102:785-791.
Ohkawa H, Ohishi N, Yagy K.  Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction . Anal Biochem . 1979;95:351-358.Article
Sprung CL, Schultz DR, Marcial E, et al.  Complement activation in septic shock patients . Crit Care Med . 1986;14:525-528.Article
Elebute EA, Stoner HB.  The grading of sepsis . Br J Surg . 1983;70:29-31.Article
Dominioni L, Dionigi R, Zanello M, et al.  Sepsis score and acute-phase protein response as predictors of outcome in septic surgical patients . Arch Surg . 1987;122:141-146.Article
Teres D.  Peer review, publication policy, and APACHE . Crit Care Med . 1989;17:S169-S172.Article
Wagner JL, Hugli TE.  Radioimmunoassay for anaphylatoxins: a sensitive method for determining complement activation products in biological fluids . Anal Biochem . 1984;136:75-88.Article
Zilow G, Sturm JA, Rother U, Kirshfink M.  Complement activation and the prognostic value of C3a in patient at risk of adult respiratory distress syndrome . Clin Exp Immunol . 1990;79:151-157.Article
Huey R, Hugli TE.  Characterization of a C5a receptor on human polymorphonuclear leukocytes (PMN) . J Immunol . 1985;135:2063-2068.
Gardinali M, Cicardi M, Agostoni A, Hugli TE.  Complement activation in extracorporeal circulation: physiological and pathological implications . Pathol Immunopathol Res . 1986;5:352-370.Article
Hohn DC, Meyers AJ, Gherini ST, Beckmann A, Markison RE, Churg AM.  Production of acute pulmonary injury by leukocytes and activated complement . Surgery . 1980;88:48-56.
Goris RJA, Boeckholtz WKF, van Bebber IPT, Nuytinck JKS, Schillings PHM.  Multiple organ failure and sepsis without bacteria: an experimental model . Arch Surg . 1986;121:897-901.Article
Faist E, Storck M, Ertel W, Mewes A.  Posttraumatic immune suppression as initiator of organ failure in shock, sepsis and organ failure . In: Schlag G, Redl H, Siegel JH, eds. Shock, Sepsis and Organ Failure . New York, NY: Springer-Verlag NY Inc; 1990:307-328.
Henson PM, Larsen CL, Webster O, Mitchell BC, Goins AJ, Henson JE.  Pulmonary microvascular alterations and injury induced by complement fragments: synergistic effect of complement activation, neutrophil sequestration and other humoral mediators . Ann N Y Acad Sci . 1982;384:287-300.Article
Ward PA, Till GO, Kunkel R, Beauchamp C.  Evidence for role of hydroxyl radical in complement and neutrophil dependent tissue injury . J Clin Invest . 1983;72:789-801.Article
Tonnesen MG, Smedly LA, Henson PA.  Neutrophil-endothelial cell interactions: modulation of neutrophil adhesiveness induced by complement fragments C5a and C5ades-Arg and formyl-methionyl-phenylalanine in vitro . J Clin Invest . 1984;74:1581-1592.Article
Taylor JC, Crawford IP, Hugli TE.  Limited degradation of the third component (C3) of human complement by human leukocyte elastase (HLE): partial characterization of C3 fragments . Biochemistry . 1977;16:3390-3396.Article
Chiara O, Giomarelli PP, Borrelli E, Casini A, Segala M, Grossi A.  Inhibition by methylprednisolone of leukocyte-induced pulmonary damage . Crit Care Med . 1991;19:260-265.Article
Gutteridge JMC.  Use of thiobarbituric acid reaction in oxygen radical chemistry . Anal Proc . 1990;27:219-221.
Bertrand Y, Pincemail J, Hanique G, et al.  Differences in tocopherollipid ratios in ARDS and non-ARDS patients . Intensive Care Med . 1989;15: 87-93.Article