Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma

Abstract

Background: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. Methods: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. Results: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. Conclusions: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

Immune dysfunction following severe trauma: A systems failure from the central nervous system to mitochondria

“…The endothelium is located at the nexus of the blood and tissues and controls the transfer of O 2 , metabolic fuels, hormones, immune cells and factors, inflammatory regulators and fluids (96)(97)(98)(99)(100)(101)(102). Trauma-induced damage to this organ is termed the endotheliopathy of trauma (EoT), which is characterized by endothelial activation, vasoactivity, loss of barrier function, leukocyte adhesion, coagulopathy, inflammation and organ dysfunction (103)(104)(105)(106)(107)(108)(109)(110). In addition, the endothelium, like the BBB, is highly sensitive to changes in blood flow and shear stress, which can alter vascular tone, tissue perfusion, exchange and permeability (111).…”

“…In 2017, Johansson and colleagues introduced a model of SHock-INduced Endotheliopathy (SHINE) to better understand the underlying pathophysiological mechanisms for critically ill patients (147). Like SHOT, they propose that shockinduced sympatho-adrenal hyperactivation is a critical driver of endothelial cell and glycocalyx damage, hypoperfusion, and 10.3389/fmed.2022.968453 subsequent hemostatic aberrations and multiorgan dysfunction (110). More recently, Henriksen reported that patients with identical trauma severity developed significantly different degrees of endothelial dysfunction, as measured by syndecan-1, and proposed a minimum of four shock-induced endotheliopathy phenotypes (148) with the differences most likely driven by a genetic component (148).…”

Injury-induced endotheliopathy: What you need to know

“…Additional recent data show that EoT is a pathophysiologic state that persists over the first 24 hours after injury and remains a significant predictor of poor outcomes throughout this time period. 14 Using innovative proteomics approaches, Krocker et al 15 have shown that EoT is associated with a unique plasma proteome signature enriched in damage-associated molecular patterns (DAMPS), inflammatory mediators, and organ-specific intracellular markers, corroborating clinical evidence linking EoT with organ damage.…”

The Neuroendothelial Axis in Traumatic Brain Injury: Mechanisms of Multiorgan Dysfunction, Novel Therapies, and Future Directions

“…Proteomic profiling may be the next generation of understanding trauma-related pathways and biomarkers. Krocker et al explored a set of proteins that best predict endotheliopathy (SDC-1 ≥ 40 ng/mL) and end-organ damage in a cohort of severely injured patients (128). On proteomic analysis, they found 52 proteins differentially expressed between the groups, with the top 10 strongly predictive for endotheliopathy.…”

“…On proteomic analysis, they found 52 proteins differentially expressed between the groups, with the top 10 strongly predictive for endotheliopathy. Of note, four DAMP proteins were found to have elevated concentrations in the endotheliopathy of trauma group, which have been shown to mediate a multitude of endothelial impairment and permeability, inflammatory responses, and end-organ injury (128). Li et al (129) conducted a secondary analysis of trauma patients included in the Prehospital Air Medical Plasma and Study of Tranexamic Acid During Air and Ground Medical Prehospital Transport trials using high-dimensional proteomics.…”