Functions of the complement components C3 and C5 during sepsis - PubMed (original) (raw)

Functions of the complement components C3 and C5 during sepsis

Michael A Flierl et al. FASEB J. 2008 Oct.

Abstract

Activation of the complement system is a key event in the pathogenesis of sepsis. Nevertheless, the exact mechanisms remain inadequately understood. In the current study, we examined the role of complement C3 and C5 in sepsis in wild-type and C3- or C5-deficient mice induced by cecal ligation and puncture. When compared to wild-type mice, C5(-/-) showed identical survival, and C3(-/-) presented significantly reduced survival. Interestingly, this was associated with significant decreases in plasma levels of proinflammatory mediators. Moreover, although septic C3(-/-) animals displayed a 10-fold increase of blood-borne bacteria, C5(-/-) animals exhibited a 400-fold increase in bacteremia when compared to wild-type mice. These effects were linked to the inability of C5(-/-) mice to assemble the terminal membrane attack complex (MAC), as determined by complement hemolytic activity (CH-50). Surprisingly, although negative control C3(-/-) mice failed to generate the MAC, significant increases of MAC formation was found in septic C3(-/-) mice. In conclusion, our data corroborate that hemolytic complement activity is essential for control of bacteremia in septic mice. Thus, during sepsis, blockade of C5a or its receptors (rather than C5) seems a more promising strategy, because C5a-blockade still allows for MAC formation while the adverse effects of C5a are prevented.

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Figures

Figure 1.

Figure 1.

Survival of WT, C3−/−, and C5−/− mice following CLP. Mice were subjected to CLP. Kaplan-Meier survival curves were analyzed for WT, C3−/−, and C5−/− mice (_n_=15 per group and condition). Intermediate-grade CLP (A) was initiated by ligation of 50% of the cecum, whereas during high-grade CLP (B), 75% of the cecum was ligated.

Figure 2.

Figure 2.

Analysis of CFUs, neutrophil counts, and plasmatic C5a levels in septic WT, C3−/−, and C5−/− mice. A) Blood samples were harvested by cardiac puncture 0, 6, 12, 24, and 48 h after induction of CLP, plated on sheep-blood agar, incubated under aerobic conditions and analyzed for CFUs. B) Comparison of CFUs in negative control WT mice or WT, C3−/−, and C5−/− mice 24 h after CLP. C) CFU levels comparing WT and C6-depleted animals under negative control conditions or 24 h after CLP. D) Neutrophil counts were obtained from WT, C3−/−, and C5−/− mice under negative control conditions or 24 h after initiation of CLP. E) Plasma levels of C5a in WT, C3−/−, and C5−/− mice following CLP as determined by ELISA.

Figure 3.

Figure 3.

Analysis of thrombin activity in WT and C3−/− mice following CLP. Plasma was obtained from C3−/− or WT mice by cardiac puncture and subjected to analysis for thrombin activity as a function of time after CLP.

Figure 4.

Figure 4.

Analysis of serum complement hemolytic activity (CH-50) in healthy and septic WT, C6-depleted, C3−/−, and C5−/− mice. Sera were obtained by cardiac puncture and subjected to CH-50 analysis as described in the Methods. A–C) Analysis of wild-type (A), C3−/− (B), or C5−/− (C) animals under negative control and septic conditions. D) Effect of C6-depleting antibody or isotype IgG on CH-50 values. E) Comparison of CH-50 values of C6-depleted mice under negative control conditions or following CLP. F) Actual CH-50 values of the curves A_–_E, including display of statistical differences.

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