The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure (original) (raw)

1994, Journal of Experimental Medicine

We investigated whether the third component of complement (C3) is involved in the pathophysiology of endotox~c shock, and ~f it is involved, whether it plays a protective role or whether it mediates shock and multiple organ failure. In a prospective, controUed 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, =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 prophyhctic 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 m 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, C3deficient 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 ammotransferase) than controls, (aU P <0.05). After E. cob endotoxin infusion, C3-ddiclent ammals compared to controls had significantly less of a decrease in mean C5 levds (P <0.01), but similar (P = NS) increases in circulating tumor necrosis factor levels, bronchoalveolar lavage nentrophils, and protein, and similar (P-NS) decreases in blood lenkocytes and platelets. Two of stx C3deficient ammals and two of six controls died. In summary, after intravenous infusion of E. coli endotoxm, 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 m the host defense against E. coli endotoxic shock. ,•pproximately 400,000 patients develop sepsis each year in the United States. Of these, 50% develop septic shock and multiple organ damage, which is associated with a mortality rate of 50-70% (1). In the pathogenesis of sepsis, endotoxin interacts with a number of endogenous mediators such as complement and clotting systems, bradykinin, arachidonic acid, TNF, and a variety of other cytokines (2). Each