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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Editorial Comment
The anti-inflammatory potential of selective cholinergic agonists.
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Resuscitation with fresh frozen plasma (FFP) is associated with improved outcomes after hemorrhagic shock. Many trauma centers are using thawed plasma that has been stored for up to 5 days at 4°C (refrigeration), yet the effect of refrigeration on FFP is relatively unknown. Previously, our group showed that refrigeration of FFP changed its coagulation factors and diminished its beneficial effects on endothelial cell (EC) function and resuscitation in an animal model of hemorrhagic shock. ⋯ Inhibition of TGF-β type I receptor blocked FFP-induced Smad3 signaling in EC cells and restored the effectiveness of day 5 FFP on EC migration to a comparable level seen in day 0 FFP. These data suggest that the increased TGF-β levels during FFP refrigeration contribute to the deterioration of refrigerated FFP's effects on EC migration. This study identifies a novel molecular mechanism contributing to the reduced efficacy of refrigerated FFP.
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Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is one of the critical inhibitory regulators of early stages of T-cell activation and proliferation, which opposes the actions of CD28-mediated costimulation. Anti-CTLA-4 therapy has been effective clinically in enhancing immunity and improving survival in patients with metastatic cancer. Sepsis is a lethal condition that shares many of the same mechanisms of immune suppression with cancer. ⋯ At high dose, anti-CTLA-4 worsened survival, but at lower doses, survival was significantly improved. Survival in sepsis depends on the proper balance between the proinflammatory and anti-inflammatory/immunologic systems. Anti-CTLA-4-based immunotherapy offers promise in the treatment of sepsis, but care must be used in the timing and dose of administration of the drug to prevent adverse effects.
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Trauma registers show that hypothermia (HT) is an independent risk factor for death during hemorrhagic shock, although experimental animal studies indicate that HT may be beneficial during these conditions. However, the animal models were not designed to detect the expected increase in bleeding caused by HT. In a new model for uncontrolled bleeding, 40 Sprague-Dawley rats were exposed to a standardized femoral artery injury and randomized to either normothermia or HT. ⋯ Total rebleeding volume was significantly larger in the hypothermic group, even at body temperatures greater than 35°C. We conclude that the risk of rebleeding from a femoral injury is greater in the presence of cooling and HT. The larger rebleeding volumes seen even at body temperatures greater than 35°C indicate that factors other than temperature-induced coagulopathy also contributed to the increased hemorrhage.
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Hyporeactivity to vasoconstrictors is one of the clinical manifestations of sepsis in man and experimental animals. The objective of the investigation was to examine whether atorvastatin can prevent hyporeactivity to norepinephrine (NE) in mouse aorta in sepsis, and if so, what are the mechanisms involved. Sepsis in mice was induced by cecal ligation and puncture. ⋯ Atorvastatin pretreatment, however, prevented the decrease in α(1D)-adrenoceptor mRNA expression in septic animals. In conclusion, atorvastatin seems to prevent hyporeactivity to vasoconstrictor NE in the aorta from septic mice through attenuation of overproduction of NO as well as improved α(1D)-adrenoceptor mRNA expression. The findings of the present study may explain the beneficial effects of atorvastatin on improved hemodynamic functions in sepsis.