Complement and Its Consequences in Sepsis

Objectives

This chapter will:

1.
Describe products of complement activation during sepsis.
2.
Demonstrate protective effects of blocking antibodies to C5a, together with its structural details, in the setting of sepsis.
3.
Explain pathophysiologic events related to complement activation that develop during sepsis and acute lung injury, and protection against tissue damage and lethality in C5aR knockout mice or blockage of C5a receptors.

Robust activation of complement occurs in sepsis in humans and animals. Most information in septic animals is related to the use of cecal ligation and puncture (CLP), which induce polymicrobial sepsis in mice and rats. Complement activation occurs via the classical and the alternative pathways of activation, together with activation of the lectin pathway, although very little is known about how and why complement activation is occurring in the setting of sepsis. Complement activation includes products derived from C3 (e.g., C3b, iC3b) and C5 (C5a, C5b, and C5b-9, the membrane attack complex). All of these products have proinflammatory properties. Obviously, the appearance of complement activation products is not specific for sepsis, because similar products can appear in plasma after endotoxemia, burn injury, autoimmune diseases (such as systemic lupus erythematosus); after ischemia-reperfusion injury; and in many other conditions. Other biomarkers of sepsis include a long list of factors (e.g., precalcitonin, cytokines and chemokines, histones, lactate), but these are nonspecific for sepsis, although their plasma levels often correlate with the intensity of the sepsis condition.

Complement Activation Products in Plasma During Sepsis

As indicated above, complement activation products usually appear in the plasma of humans and animals with sepsis. Using C3 or C4 KO mice, RAG2 KO mice (which lack T and B cells) or mice infused with the C1 esterase inhibitor, involvement of the classical pathway has been demonstrated in sepsis. Engagement of the alternative pathway in sepsis has been suggested by the presence of activated factors B and D in plasma, which are critical factors that promote complement activation. Finally, activation of the mannose-binding lectin (MBL) pathway has been suggested by the plasma presence of activated MBL-associated serine protease-2 (MASP-2) in septic mice. Although lipopolysaccharide frequently has been incriminated in sepsis, there is no consensus about its role in sepsis, either in mice or in humans. Furthermore, “sterile sepsis” (which develops after nonpenetrating polytrauma, hemorrhagic shock, or after ischemia-reperfusion injury and after chemical injury) shows similar patterns of complement activation in the absence of an identifiable infectious pathogen. Infectious sepsis features the appearance of pathogen-associated molecular patterns (PAMPs) with Toll-like receptors (TLRs) present on surfaces of cells (e.g., phagocytes, endothelial cells). Such interactions trigger production of proinflammatory mediators (IL-1β, TNF, IL-6). In contrast, “sterile” sepsis (described above) often mimics infectious sepsis but in the absence of infectious agents. These pathways also lead to engagement of danger-associated molecular patterns (DAMPs), which are endogenous to cells and engage intracellular nucleotide oligomerization domain (NOD)-like receptors (NLRs). Examples of DAMPs that engage NLRs are heat shock proteins, uric acid crystals, hyaluronan, mitochondrial DNA, and defensins. Complement activation and proinflammatory mediator appearance usually occur together, similar to outcomes that develop when the TLR system is activated by agents such as bacterial lipopolysaccharide (LPS).

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