Complement Activation and the Production of Inflammatory Mediators During the Treatment of Severe Sepsis in Humans

Abstract

Sepsis or septic shock is frequently associated with activation of the complement system, coagulation and fibrinolytic changes and the release of several cytokines. In this study we analyzed the relation of complement activation to the inflammatory mediators, hemodynamic and biochemical parameters and severity of illness and outcome in 20 consecutive patients with clinically defined sepsis. Levels of C3a and C3d were elevated in 90% of the patients (median levels 0.19 mg/l and 8.6 mg/l respectively) in comparison to 14% and 42%, respectively of 7 patients with non-septic shock. Levels of C4 were decreased in only 1 of the 20 septic patients. Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, Levels of TNF and IL-6 were elevated in 94% and 100% of the patients, respectively (median levels 122 ng/l and 1300 U/ml) and were clearly interrelated (r = 0.67, p less than 0.01). C3a levels correlated with the APACHE II score (r = 0.57, p less than 0.05) and high C3a levels were associated with fatal outcome (p less than 0.05). C3a was also correlated inversely with mean arterial pressure (r = 0.50, p less than 0.01). Levels of complement C3a and C3d significantly correlated with levels of plasminogen activator inhibitor-1 (PAI) and correlated inversely with AT-III levels. We found no correlation between these complement products and leukocyte counts or lactate levels, nor was there a correlation between C3a or C3d and the cytokines TNF and IL-6. Levels of C3a and C3d did not decrease significantly during the first 24 h of treatment, in contrast to a clear decrease in IL-6 levels in all patients and a decrease in TNF in the surviving patients. TNF levels remained stable or increased in the non-survivors. We conclude that both the complement system and the cytokine system are involved in the pathogenesis of septic shock and may be involved in the development of some of the fatal complications like hypotension and disseminated intravascular coagulation.

New Rationale for Glucocorticoid Treatment in Septic Shock

“…During an observation period of 14 days, nonsurvivors of sepsis had significantly higher NF-kB activity (P <0.001) in their peripheral mononuclear cells than did survivors 52 . In agreement, several studies have reported that nonsurvivors of sepsis [53][54][55][56][57][58][59] and ARDS 59-64 exhibit exaggerated and protracted elevation of circulating pro-inflammatory cytokine levels. In patients with sepsis-induced ARDS we found 59 that elevated pro-inflammatory cytokine levels on day one predicted a persistent elevation over time suggesting that loss of autoregulation is an early event in the course of lethal sepsis.…”

The role of the host defence response in the progression and outcome of ARDS: pathophysiological correlations and response to glucocorticoid treatment

“…Furthermore, in nonsurvivors the BAL:plasma ratio for TNF-α, IL-1Β, IL-6 and IL-8 remained unchanged throughout the course of the disease, while it rapidly decreased in survivors [50]. Other groups have also reported nonsurvivors of ARDS or sepsis to have persistent elevation of inflammatory cytokines (table 4) other components of the HDR (i.e., PLA 2 , leukotrines and complement) over time [51,67,[88][89][90]. This finding is important to understanding why treatment modalities of limited duration may be ineffective in ARDS.…”

“…Patients with ARDS also have marked and prolonged systemic procoagulant activity and rapid exhaustion of the fibrinolytic system [105]. In sepsis, high levels of PAI-1 are associated with a poor prognosis [106] and correlate with TNF, IL-6 and complement 3a levels [51]. Virtually all ARDS patients have increased circulating FDP levels [107].…”

Complement Activation, C3 and Interleukin-6 Levels as Prognostic Markers in Polytraumatized Patients

“…[1,3,4] Many of these alterations have been shown to correlate with an increased rate of sepsis in the posttraumatic and post-operative periods. [5,6] Recently, it has become clear that a cytokine Interleukin-6, earlier known as hybridoma growth factor, is involved in systemic changes associated with tissue injury and infection. [7,8,9] IL-6 is released by damaged tissue and induces the synthesis of proteins in the liver (acute phase proteins) that protect the host against inflammatory reactions, hence has been rightly called the "alarm hormone".…”