Combined inhibition of the complement component C5 and the TLR-coreceptor CD14 alters the posttraumatic response in fracture hematoma in a porcine polytrauma model

TL;DR

Inhibiting C5 and CD14 in a pig model of polytrauma reduced inflammation both in the blood and at the fracture site.

Contribution

This study shows that combined C5 and CD14 inhibition reduces pro-inflammatory proteins in both systemic and local post-traumatic responses.

Findings

Pro-inflammatory proteins like IL-1β, IL-6, and IFN-α were significantly reduced in treated pigs.

Soluble TLR4 increased in plasma and fracture hematoma after C5/CD14 inhibition.

Inflammation levels were lower in plasma compared to the fracture hematoma.

Abstract

Polytrauma is characterized by high mortality and morbidity rates, partly due to the post-traumatic immune response. This follow-up study investigated the effect of combined inhibition of complement factor 5 (C5) and CD14 on systemic (plasma) and local (fracture hematoma) protein levels in a porcine polytrauma model.

18 male pigs (sus scrofa) were used for this study: a control group (n=6), and two groups that were subjected to standardized polytrauma, followed by standard treatment (intramedullary nailing; n=8) or standard treatment with C5/CD14 inhibition therapy (n=4). Plasma and fracture hematoma samples were collected at specified time points and the expression levels of proteins related to the post-traumatic immune response and fracture healing were determined using enzyme-linked immunosorbent assays.

Pro-inflammatory proteins such as IL-1β, IL-6, and IFN-α were significantly reduced in both plasma and fracture hematoma samples at 72 h after trauma in the treated vs. the non-treated group. Soluble TLR4, a possible inhibitor of cell membrane TLR4, was increased in both the plasma and the fracture hematoma following therapy, suggesting that TLR4 was released from the cell membrane to the fluid phase.

These findings show that systemic C5/CD14 inhibition effectively reduced the concentration of several pro-inflammatory proteins in the systemic circulation and locally, at the fracture site, in the fracture hematoma. The levels in the plasma were in line with those in the fracture hematoma, albeit that they were markedly lower in the plasma compared to the fracture hematoma.

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