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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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.
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Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) has been shown to promote cellular energetic collapse and cellular necrosis in various forms of critical illness. Most of the evidence implicating the PARP pathway in disease processes is derived from preclinical studies. With respect to PARP and burns, studies in rodent and large animal models of burn injury have demonstrated the activation of PARP in various tissues and the beneficial effect of its pharmacological inhibition. ⋯ We conclude that human burn injury is associated with the activation of PARP. We hypothesize that this response may contribute to the inflammatory responses and cell dysfunction in burns. Some of the clinical benefit of propranolol in burns may be related to its inhibitory effect on PARP activation.
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We hypothesized that circulating levels of lipid peroxidation products in patients with severe sepsis are associated with the development of pulmonary, renal, hepatic, circulatory, and coagulation failure. Plasma levels of F2-isoprostanes and isofurans were measured by mass spectroscopy on intensive care unit day 2 in 50 critically ill patients with severe sepsis. Plasma F2-isoprostane levels were higher in patients who developed renal failure compared with those who did not (65 pg/mL [interquartile range {IQR} 44-112] vs. 44 pg/mL [IQR 29-54], P = 0.009) as were isofuran levels (1,223 pg/mL [IQR 348-2,531] vs. 329 pg/mL [IQR 156-1,127], P = 0.009). ⋯ Patients with isoprostane levels above the 25th percentile had higher mortality (42%) compared with patients with levels below the 25th percentile (8%, P = 0.03). Plasma levels of F2-isoprostanes and isofurans are associated with renal, hepatic, and coagulation failure, but not with circulatory or pulmonary failure in severe sepsis, suggesting that lipid peroxidation is a prominent feature of septic multisystem organ failure. Plasma isoprostanes and isofurans may be useful for monitoring oxidative stress in treatment trials of antioxidant therapies in severe sepsis.