Abstract
Despite significant improvements in injury prevention and emergency response, injury-related death and morbidity continues to increase in the US and worldwide. Patients with trauma, invasive operations, anti-cancer treatment, and organ transplantation produce a host of danger signals and high levels of pro-inflammatory and pro-thrombotic mediators, such as damage-associated molecular patterns (DAMPs) and extracellular vesicles (EVs). DAMPs (e.g., nucleic acids, histone, high-mobility group box 1 protein, and S100) are molecules released from injured, stressed, or activated cells that act as endogenous ligands of innate immune receptors, whereas EVs (e.g., microparticle and exosome) are membranous vesicles budding off from plasma membranes and act as messengers between cells. DAMPs and EVs can stimulate multiple innate immune signaling pathways and coagulation cascades, and uncontrolled DAMP and EV production causes systemic inflammatory and thrombotic complications and secondary organ failure (SOF). Thus, DAMPs and EVs represent potential therapeutic targets and diagnostic biomarkers for SOF. High plasma levels of DAMPs and EVs have been positively correlated with mortality and morbidity of patients or animals with trauma or surgical insults. Blocking or neutralizing DAMPs using antibodies or small molecules has been demonstrated to ameliorate sepsis and SOF in animal models. Furthermore, a membrane immobilized with nucleic acid-binding polymers captured and removed multiple DAMPs and EVs from extracellular fluids, thereby preventing the onset of DAMP- and EV-induced inflammatory and thrombotic complications in vitro and in vivo. In this review, we will summarize the current state of knowledge of DAMPs, EVs, and SOF and discuss potential therapeutics and preventive intervention for organ failure secondary to trauma, surgery, anti-cancer therapy, and allogeneic transplantation.
Highlights
KEY CONCEPTSSecondary Organ Failure: Dysfunction or injury of organs remote from the primary injury site is often the sequelae of the host’s dysregulated immune response
About five million people die from injuries worldwide every year [1]
Secondary organ failure (SOF) is most prevalent in patients with traumatic injuries, SOF occurs in patients with sterile insults such as invasive surgery or anti-cancer treatment [4, 5]
Summary
Secondary Organ Failure: Dysfunction or injury of organs remote from the primary injury site is often the sequelae of the host’s dysregulated immune response. Immunothrombotic Agents: Certain cellular components released from stressed, damaged, or dead cells can activate both innate immune receptors and coagulation cascades, leading to inflammatory response and blood coagulation, respectively. Feed-Forward Loop: In solid organ transplantation, graft injury from infiltrating inflammatory cells leads to further DAMP release, intensified inflammation, and exacerbation of graft injury. Vicious Cycle of Injury and DAMP/EV Production: Polytrauma or invasive surgery will produce circulating pro-inflammatory and pro-thrombotic mediators that cause microinjury and de novo release of the pro-inflammatory and pro-thrombotic mediators in remote organs, thereby developing SOF
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