title: The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure.
abstract: We investigated whether the third component of complement (C3) is involved in the pathophysiology of endotoxic shock, and if it is involved, whether it plays a protective role or whether it mediates shock and multiple organ failure. In a prospective, controlled investigation, six Brittany spaniels that were homozygous for a genetically determined deficiency of C3 (C3 deficient, < 0.003% of normal serum C3 levels) and six heterozygous littermates (controls, approximately 50% of mean normal serum C3 level) were given 2 mg/kg of reconstituted Escherichia coli 026:B6 acetone powder as a source of endotoxin, intravenously. All animals were given similar fluid and prophylactic antibiotic therapy, and had serial hemodynamic variables obtained. After E. coli endotoxin infusion, C3-deficient animals had higher peak levels of endotoxin and less of a rise in temperature than controls (P < 0.05). During the first 4 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean central venous pressure and mean pulmonary artery pressure than controls (P < 0.02). During the first 48 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean arterial pH, left ventricular ejection fraction, and mean pulmonary capillary wedge pressure, and greater increases in mean arterial lactate, arterial-alveolar O2 gradient, and transaminases (aspartate aminotransferase and alanine aminotransferase) than controls, (all P < 0.05). After E. coli endotoxin infusion, C3-deficient animals compared to controls had significantly less of a decrease in mean C5 levels (P < 0.01), but similar (P = NS) increases in circulating tumor necrosis factor levels, bronchoalveolar lavage neutrophils, and protein, and similar (P = NS) decreases in blood leukocytes and platelets. Two of six C3-deficient animals and two of six controls died. In summary, after intravenous infusion of E. coli endotoxin, canines with C3 deficiency have decreased endotoxin clearance and worse E. coli endotoxin-induced shock and organ damage. Thus, the third component of the complement system plays a beneficial role in the host defense against E. coli endotoxic shock.
authors.affiliation: Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Quezado
authors.forename: W D
authors.initials: WD
authors.lastname: Hoffman
authors.forename: J A
authors.initials: JA
authors.lastname: Winkelstein
authors.forename: I
authors.initials: I
authors.lastname: Yatsiv
authors.forename: C A
authors.initials: CA
authors.lastname: Koev
authors.forename: L C
authors.initials: LC
authors.lastname: Cork
authors.forename: R J
authors.initials: RJ
authors.lastname: Elin
authors.forename: P Q
authors.initials: PQ
authors.lastname: Eichacker
authors.forename: C
authors.initials: C
authors.lastname: Natanson
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003176:Complement C3 / Q000172:deficiency / Q000276:immunology*; D004285:Dogs; D004731:Endotoxins / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology*; D005260:Female; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000503:physiopathology; D008099:Liver / Q000503:physiopathology; D008168:Lung / Q000503:physiopathology; D008297:Male; D009102:Multiple Organ Failure / Q000097:blood / Q000276:immunology*; D011446:Prospective Studies; D012772:Shock, Septic / Q000097:blood / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D003176:Complement C3; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli