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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Aggressive fluid or blood component transfusion for severe hemorrhagic shock may restore macrocirculatory parameters, but not always improve microcirculatory perfusion and tissue oxygen delivery. We established an ovine model of hemorrhagic shock to systematically assess tissue oxygen delivery and repayment of oxygen debt; appropriate outcomes to guide Patient Blood Management. ⋯ Non-invasive measures of tissue oxygen delivery and oxygen debt repayment are suitable outcomes to inform Patient Blood Management of hemorrhagic shock, translatable for pre-clinical assessment of novel resuscitation strategies.
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During sepsis the normal induction of circulating insulin-like growth factor-I (IGF-I) by growth hormone (GH) action on liver is attenuated, a phenomenon called hepatic GH resistance. Hepatic GH resistance can be caused by cytokine-mediated activation of the NF-κB pathway which interferes with normal GH-signaling. The afferent and efferent fibers of the vagus nerve are integral to the cholinergic anti-inflammatory pathway (CAP) which attenuates hepatic TNFα production by activating the α7 nicotinic acetylcholine receptor (α7nAChR). ⋯ The effects of sepsis on the GH/IGF-I system plasma IGF-I, IGF binding protein-1 (IGFBP-1), hepatic IGF-I, IGFBP-1, and GH receptor (GHR) mRNA and rhGH-responsiveness in mice were improved by GTS-21. Collectively these results confirm the protective effects of the anti-inflammatory CAP and α7nAChR activation in sepsis. They also provide evidence the CAP and α7nAChR activation could be used to attenuate hepatic GH resistance and anabolic failure in sepsis.
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Crush syndrome (CS) is the most common cause of deaths following earthquakes and other disasters. The pathogenesis of CS has yet to be fully elucidated. Thus, clinical choice of ideal drug treatments for CS remains deficient. ⋯ Our findings demonstrated that the severity of crush injury is causally related to extrusion pressure and increase in blood serum markers. Our identification of the biomarker and treatment candidate, α1-AGP, suggests its implication in predicting the severity of CS and its use as a mediator of CS-induced AKI, respectively.
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Acute lung injury (ALI) is caused by direct pulmonary insults and indirect systemic inflammatory responses that result from conditions such as sepsis and trauma. Alveolar macrophages are the main and critical leukocytes in the airspace, and through the synthesis and release of various inflammatory mediators critically influence the development of ALI following infection and non-infectious stimuli. ⋯ In this study, we demonstrate that memantine, a N-methyl-D-aspartic acid receptor (NMDAR) antagonist, through suppressing Ca2+ influx and subsequent ASC oligomerization inhibits macrophage Nlrp3 inflammasome activation and pyroptosis, therefore, alleviates ALI in septic mice. This finding explores a novel application of memantine, an FDA already approved medication, in the treatment of ALI, which is currently lacking effective therapy.
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Acute kidney injury (AKI) is characterized by rapid loss of excretory function and is the clinical manifestation of several disorders affecting the kidney. The aim of the present study was to investigate the mechanism of action of Secretory Leukocyte Proteinase Inhibitor (SLPI) that protects the kidneys form AKI. In vivo and in vitro experiments were performed to assess the effect of SLPI on kidney injury. ⋯ An analysis of the gene profiles of HK-2 cells treated with calcineurin inhibitors affected inflammatory and non-inflammatory pathways that were reversed by SLPI. Among them, SLPI down modulated the expression of CCL2, SLC5A3, and BECN1 but up-regulated the expression of TLR4, ATF4, ATF6, HSP90B, BBC3 SLC2A1, and TNFRSF10B. Overall, these results suggest that SLPI, in addition to its activity on immune cells, may directly target tubular epithelial cells of the kidney to mediate the nephroprotective activity in AKI.