Early release of soluble receptor for advanced glycation endproducts after severe trauma in humans

Abstract

Background: The receptor for advanced glycation endproducts (RAGE) recognizes a variety of ligands that play an important role in the posttraumatic inflammatory response. However, whether soluble RAGE (sRAGE) is released early after trauma hemorrhage in humans and whether such a release is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of this study.

Methods: One hundred sixty-eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level I Trauma center. Blood was drawn within 10 minutes of arrival to the emergency department before the administration of any fluid resuscitation. sRAGE, tumor necrosis factor-alpha, interleukin-6, von Willebrand factor, angiopoietin-2, prothrombin time, prothrombin fragments 1 + 2, soluble thrombomodulin, protein C, plasminogen activator inhibitor-1, and d-dimers (fibrin degradation products) were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared with outcome measures obtained from the electronic medical record and trauma registry.

Results: Plasma levels of sRAGE were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, early posttraumatic coagulopathy and hyperfibrinolysis, and endothelial cell activation (angiopoietin-1 and complement). Furthermore, we found that there was a significant relationship between plasma levels of sRAGE and the development of acute renal failure. This relationship was not quite significant for patients who developed acute lung injury (p = 0.11), although patients with <26 ventilator-free days had significantly higher plasma levels of sRAGE than those with >26 ventilator-free days. Finally, there was no relationship between plasma levels of sRAGE and mortality rate in trauma patients.

Conclusion: The results of this study demonstrate that the release of sRAGE in the bloodstream of trauma patients requires severe injury and is associated with coagulation abnormalities and endothelial cell and complement activation.

Figure 1. Effect of severity of injury on plasma levels of sRAGE early after trauma

Blood samples were obtained from 168 consecutive major trauma patients immediately upon admission to the hospital. Plasma levels of sRAGE correlated with the Injury Severity Score (ISS). Data are presented in quartiles, *p ≤ 0.05 based on test for rank and trend.

Figure 2. High plasma levels of sRAGE are associated with the release of markers of endothelial cell and complement activation in trauma patients

Blood samples were obtained from 168 consecutive major trauma patients immediately upon admission to the hospital. Panels A&B. Plasma levels of sRAGE are associated with increased plasma levels of Ang-2 and with increased complement activity, as indicated by elevated soluble C5b-9 plasma levels that are generated during the late phase of complement activation. Data are presented in quartiles, *p ≤ 0.05 based on test for rank and trend.

Figure 3. High plasma levels of sRAGE are associated with coagulation abnormalities in trauma patients

Blood samples were obtained from 168 consecutive major trauma patients immediately upon admission to the hospital. Panel A. Trauma patients with coagulation abnormalities (INR = international normalized ratio > 1.5) had significantly higher levels of sRAGE. *p ≤ 0.05 from patients with INR = international normalized ratio < 1.5. Panels B&D. High plasma levels of HMGB1 were associated with coagulation derangements early after trauma that are not due to coagulation factor deficiency as shown by the rise in the levels of soluble PF 1+2, a marker of thrombin generation and soluble thrombomodulin as well as a fall in protein C levels. Data are presented in quartiles, *p ≤ 0.05 based on test for rank and trend.

Figure 4. High plasma levels of sRAGE are associated with increased fibrinolytic activity in trauma patients

Blood samples were obtained from 168 consecutive major trauma patients immediately upon admission to the hospital. Panels A&B. High plasma levels of sRAGE are associated with increased fibrinolytic activity early after trauma, as shown by the plasma levels of PAI-1 and D-Dimers (fibrin degradation products). Data are presented in quartiles, *p ≤ 0.05 based on test for rank and trend.

Figure 5. High plasma levels of sRAGE are associated with less ventilator-free days and acute renal failure in trauma patients

Panel A. Trauma patients with less ventilator free days (VFD) and acute renal failure (ARF) had significantly higher plasma levels of sRAGE. Data are mean ± SD; *p ≤ 0.05 compared to patients without organ injury or with more than 26 VFD. Panel B. There was no significant relationship between plasma levels of sRAGE and mortality rate after severe trauma. Data are mean ± SD.