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.

Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs

“…Interestingly, and in line with our previous in vitro findings in human whole blood ( 15 ), we discovered that air embolism predominantly activated C3 with only a minor C5 activation, contrary to what is otherwise observed in general when complement is activated, for example, by bacteria or damage or pathogen-associated molecular patterns. The C5a-C5aR axis is known to play an important role in complement-mediated thromboinflammation associated with a wide array of diseases ( 27 , 30 ), and the monoclonal anti-C5 antibody eculizumab has been used clinically for many years to treat complement-driven diseases, such as paroxysmal nocturnal hemoglobinuria and atypical hemorrhagic uremic syndrome ( 31 ). C3a receptors have been shown on both platelets and activated astrocytes, neutrophils, and monocytes ( 32 , 33 ), and we have previously shown how C3 inhibition attenuates air-induced thromboinflammation ( 15 ).…”

“…The TNF mRNA expression did not differ between the groups. In line with the mRNA findings, the median lung tissue cytokines measured as protein in pigs receiving air infusion compared to sham animals were: IL-1b 302 pg/mL (IQR 190-437) versus 107 pg/ mL (IQR 66-120), IL-6 644 pg/mL (IQR 358-1094) versus 25 pg/ mL (IQR 23-30), IL-8 203 pg/mL (IQR 81-377) versus 21 pg/mL (IQR [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], and TNF 113 pg/mL (IQR 96-147) versus 16 pg/mL (IQR 13-22) (all p<0.001) (Figure 4C). Thus, TNF increased as measured by protein but not by mRNA.…”

“…In pigs that received air infusion, baseline median TAT was 35 µg/mL (IQR [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. TAT increased after 180 minutes of air infusion and continued to increase throughout the experiments (Figure 5D).…”

“…C3a increased from 21 ng/mL to 67 (39-84) (p<0.001), whereas TCC increased only modestly (p=0.02). TAT increased from 35 µg/mL (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42) to 51 (38-89) (p=0.002). ROTEM changed during first 120 minutes: Clotting time decreased from 613 seconds (531-677) to 538 (399-620) (p=0.006), clot formation time decreased from 161 seconds to 124 (83-162) (p=0.02) and a-angle increased from 62 degrees (57-68) to 68 (62-74) (p=0.02).…”

Complement & disease: out of the shadow into the spotlight

“…The recent pandemic crisis with thousands of patients suffering from a severe form of COVID-19 that caused extensive inflammatory and thrombotic complications raised the awareness that hyperactivation of our host defense pathways can rapidly turn from protective into destructive functions. In their review, Mannes et al show that such massive complement activation events reach far beyond COVID-19 but are at the center of many systemic inflammatory response syndrome (SIRS) disorders, including sepsis, trauma, and burn injury [2]. In such cases, complement is performing its designated function by reacting to pathogen-and/or damageassociated molecular patterns but to such an extent that the generated effector causes host tissue damage and contributes to organ failure.…”