Shock : molecular, cellular, and systemic pathobiological aspects and therapeutic approaches : the official journal the Shock Society, the European Shock Society, the Brazilian Shock Society, the International Federation of Shock Societies
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Danger-associated molecular patterns (DAMPs) that are released by injured, threatened, or dead cells, or that originate from the extracellular matrix, influence the immune system. This is of great relevance in critically ill patients, in whom trauma or surgery-related cell damage, hypoxia, ischemia, and infections can result in extensive release of DAMPs. ⋯ In the present review, we provide an overview of several well known DAMPs (high-mobility group box 1, heat-shock proteins, s100 proteins, nucleic acids, and hyaluronan) and their effects on the immune system. Furthermore, we discuss the role of DAMPs as markers or therapeutic targets in several conditions frequently encountered in critically ill patients, such as sepsis, trauma, ventilator-induced lung injury, and cardiac arrest.
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The pathophysiology of burn injuries is tremendously complex. A thorough understanding is essential for correct treatment of the burned area and also to limit the appearance of organ dysfunction, which, in fact, is a key determinant of morbidity and mortality. ⋯ Research into biomarkers may help to improve the prognosis of patients with severe burn injury. The aim of the present clinical review is to discuss new evidence of the value of biomarkers in this setting.
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We have demonstrated hemorrhagic shock "priming" for the development of indirect acute respiratory distress syndrome (iARDS) in mice following subsequent septic challenge, and show pathology characteristic of patients with iARDS, including increased lung microvascular permeability and arterial PO2/FI02 reduced to levels comparable to mild/moderate ARDS during the 48 h following hemorrhage. Loss of endothelial cell (EC) barrier function is a major component in the development of iARDS. EC growth factors, Angiopoietin (Ang)-1 and 2, maintain vascular homeostasis via tightly regulated competitive interaction with tyrosine kinase receptor, Tie2, expressed on ECs. ⋯ In this study we show that Ang-2 in lung tissue and plasma spikes following hemorrhage (priming) and remain elevated at sepsis induction. In addition, that transient inhibition of Ang-2 function immediately following hemorrhage, suppressing priming, but not following sepsis, impacts the development of iARDS in our model. Our data demonstrate that selective temporal blockade of Ang-2 function following hemorrhagic shock priming significantly improved PO2/FIO2, decreased lung protein leak and indices of inflammation, and improved 10-day survival in our murine model for the development iARDS.
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Increased thrombin generation in injured patients possibly contributes to early consumption of coagulation factors, exacerbating hemorrhage. Identifying optimal resuscitation products for restoring plasma homeostasis following injury is important for improving management of these patients. ⋯ HS in rats is associated with increased thrombin generation and resuscitation with FFP, not LR, reverses hypercoagulability. Dilution of trauma patient plasma with LR or FFP yielded similar results; however, the modulatory effects of FFP were attenuated when AT was absent. Importantly, FFP reduced thrombin generation in hypercoagulable patient plasma, but slightly increased thrombin generation in hypocoagulable patient plasma. Thus, FFP restores hemostatic balance following trauma and HS which is, in part, by delivering AT.
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Gastrointestinal barrier dysfunction is associated with the severity and prognosis of sepsis. Hydrogen gas (H2) can ameliorate multiple organ damage in septic animals. Ras homolog gene family member A (RhoA) and mammalian diaphanous-related formin 1 (mDia1) are important to regulate tight junction (TJ) and adherens junction (AJ), both of which determine the integrity of the intestinal barrier. ⋯ Rho inhibitor C3 exoenzyme mitigated LPS-induced barrier breakdown. Furthermore, H2-rich medium increased mDia1 expression, and mDia1 knockdown abolished protections of H2 on barrier permeability. mDia1 knockdown eliminated H2-induced benefits for occludin and E-cadherin. These findings suggest that H2 improves LPS-induced hyperpermeability of the intestinal barrier and disruptions of TJ and AJ by moderating RhoA-mDia1 signaling.