Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis

Abstract

Complement is one of the most ancient defense systems. It gets strongly activated immediately after acute injuries like trauma, burn, or sepsis and helps to initiate regeneration. However, uncontrolled complement activation contributes to disease progression instead of supporting healing. Such effects are perceptible not only at the site of injury but also systemically, leading to systemic activation of other intravascular cascade systems eventually causing dysfunction of several vital organs. Understanding the complement pathomechanism and its interplay with other systems is a strict requirement for exploring novel therapeutic intervention routes. Ex vivo models exploring the cross-talk with other systems are rather limited, which complicates the determination of the exact pathophysiological roles that complement has in trauma, burn, and sepsis. Literature reporting on these three conditions is often controversial regarding the importance, distribution, and temporal occurrence of complement activation products further hampering the deduction of defined pathophysiological pathways driven by complement. Nevertheless, many in vitro experiments and animal models have shown beneficial effects of complement inhibition at different levels of the cascade. In the future, not only inhibition but also a complement reconstitution therapy should be considered in prospective studies to expedite how meaningful complement-targeted interventions need to be tailored to prevent complement augmented multi-organ failure after trauma, burn, and sepsis.This review summarizes clinically relevant studies investigating the role of complement in the acute diseases trauma, burn, and sepsis with important implications for clinical translation.

Keywords: Burn; Clinical translation; Complement activation; Sepsis; Systemic inflammation; Thromboinflammation; Trauma.

Figure 1.

Complement activation after burn injury. Burn injury triggers the release of damage associated molecular patterns (DAMPs) and increases the susceptibility for microbial associated molecular pattern (MAMP) exposure, thus elevating the risk for sepsis. Complement activation takes place at the burn site, locally increasing vascular permeability and promoting infiltration of immune cells. Massive anaphylatoxin release also induces widespread effects, especially affecting the lungs and the heart. CP: classical pathway, LP: Lectin pathway, RBC: red blood cell.

Figure 2.

From acute injury to multi organ dysfunction. Acute injuries with distinct DAMP/MAMP profile can induce an unbalanced complement activation not only locally but also systemically. A tight linkage to other systems of the innate immune system means that these branches are eventually also activated resulting in a state often called thromboinflammation. The consequences are multidimensional, eliciting effects on various vital organs and worsen the patient‘s outcome. The sequential related organ failure assessment score (SOFA) and especially the quick SOFA (qSOFA, comprising the organs heart, CNS and lungs) provides a basis for the evaluation of a patient‘s septic state. MODS: multi organ dysfunction syndrome.