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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In human sepsis, little is known about the relationships between complement activation and the clinical characteristics of sepsis, including disseminated intravascular coagulation (DIC), interventions, and prognosis. ⋯ The degree of complement activation is related to DIC, severity, intensive interventions, and mortality. Further studies are needed to confirm the usefulness of SC5b-9 for stratifying sepsis patients.
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Outcomes variables for research on sepsis have centered on mortality and changes in the host immune response. However, a recent task force (Sepsis-3) revised the definition of sepsis to "life-threatening organ dysfunction caused by a dysregulated host response to infection." This new definition suggests that human studies should focus on organ dysfunction. The appropriate criteria for organ dysfunction in either human sepsis or animal models are, however, poorly delineated, limiting the potential for translation. ⋯ We further examine instances where overlap between human sepsis and CLP is sufficient to identify translational endpoints. Additional verification may demonstrate that these endpoints are applicable to other animals and to other sepsis models, for example, pneumonia. We believe that the use of these proposed measures of organ dysfunction will facilitate mechanistic studies on the pathobiology of sepsis and enhance our ability to develop animal model platforms to evaluate therapeutic approaches to human sepsis.
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Circulatory shock is a life-threatening disorder that is associated with high mortality, with a state of systemic and tissue hypoperfusion that can lead to organ failure, including the brain, where altered mental state is often observed. We hypothesized that cerebral autoregulation (CA) is impaired in patients with circulatory shock. ⋯ These results suggest that circulatory shock is often associated with impaired CA and that the severity of CA alterations is correlated with the degree of multiple organ failure, reinforcing the need to monitor cerebral hemodynamics in patients with circulatory shock.
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Mortalin/GRP75 (glucose regulated protein 75), a member of heat shock protein 70 family of chaperones, is involved in several cellular processes including proliferation and signaling, and plays a pivotal role in cancer and neurodegenerative disorders. In this study, we sought to determine the role of mortalin/GRP75 in mediating vascular inflammation and permeability linked to the pathogenesis of acute lung injury (ALI). In an aerosolized bacterial lipopolysaccharide inhalation mouse model of ALI, we found that administration of mortalin/GRP75 inhibitor mean kinetic temperature-077, both prophylactically and therapeutically, protected against polymorphonuclear leukocytes influx into alveolar airspaces, microvascular leakage, and expression of pro-inflammatory mediators such as interleukin-1β, E-selectin, and tumor necrosis factor TNFα. ⋯ Mechanistic analysis in EC revealed that inactivation of mortalin/GRP75 interfered with the binding of the liberated NF-κB to the DNA, thereby leading to inhibition of downstream expression of adhesion molecules, cytokines, and chemokines. Importantly, thrombin-induced Ca signaling and EC permeability were also prevented upon mortalin/GRP75 inactivation/depletion. Thus, this study provides evidence for a novel role of mortalin/GRP75 in mediating EC inflammation and permeability associated with ALI.