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The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ
Z M Quezado1, W D Hoffman, J A Winkelstein
1Critical Care Medicine Department, National Institutes of Health, Bethesda, Maryland 20892.
Insights
Complement component 3 (C3) deficiency worsens endotoxic shock in canines, indicating a protective role for C3 in host defense against E. coli endotoxin. This study highlights C3
Area of Science:
- Immunology
- Pathophysiology
- Complement System
Background:
- The role of the third component of complement (C3) in endotoxic shock remains unclear.
- Understanding C3's function is crucial for developing targeted therapies against sepsis.
- Endotoxic shock involves complex immune responses and potential organ damage.
Purpose of the Study:
- To investigate the involvement of C3 in endotoxic shock pathophysiology.
- To determine if C3 plays a protective role or mediates shock and organ failure.
- To assess the impact of C3 deficiency on endotoxin clearance and hemodynamic stability.
Main Methods:
- A prospective, controlled study using C3-deficient and heterozygous control Brittany spaniels.
- Intravenous administration of Escherichia coli endotoxin to all animals.
- Serial monitoring of hemodynamic variables, endotoxin levels, temperature, and organ damage markers.
Main Results:
- C3-deficient canines exhibited impaired endotoxin clearance and exacerbated shock.
- Significantly greater decreases in central venous pressure, pulmonary artery pressure, and arterial pH were observed in C3-deficient animals.
- C3 deficiency led to worse organ damage, indicated by reduced left ventricular ejection fraction and elevated transaminases and lactate.
Conclusions:
- The third component of complement (C3) plays a crucial beneficial role in host defense against E. coli endotoxic shock.
- C3 deficiency results in poorer outcomes, including increased shock severity and organ damage.
- These findings underscore the protective function of C3 in managing endotoxin-induced inflammatory responses.
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.