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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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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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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The pathophysiology of sepsis-induced acute kidney injury remains poorly understood. As changes in renal perfusion and oxygenation have been shown, we aimed to study the short-term effects of endotoxemia on microvascular and interstitial oxygenation in the cortex and medulla, in conjunction with global and renal hemodynamics. In a 4-h rat model of endotoxemia, we simultaneously assessed renal artery blood flow and microvascular and interstitial oxygen tensions in the renal cortex and medulla using ultrasonic flowmetry, dual wavelength phosphorimetry, and tissue oxygen tension monitoring, respectively. ⋯ At study end, urine output was significantly decreased despite a maintained oxygen consumption rate. In this 4-h rat model of endotoxemia, total renal oxygen consumption and the gradient between microvascular PO₂ and tissue oxygen tension remained unaltered, despite falls in renal perfusion and oxygen delivery and urine output. Taken in conjunction with the decrease in urine output, our results could represent either a functional renal impairment or an adaptive response.
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A growing number of reports indicate that bioenergetic failure plays a crucial role in the development of multiple organ failure during sepsis. Our previous results showed that the suppression of IF1 (mitochondrial ATPase inhibitor protein) expression and subsequent elevated mitochondrial F(o)F₁-ATPase activity might contribute to the bioenergetic failure in the liver during sepsis, and the influence of the decreased transcriptional level of IF1 might be an important factor. In this study, we investigated the interaction of IF1 protein expression and hypoxia-inducible factor 1 (HIF-1), a transcription factor that is correlated with the inflammatory status in sepsis. ⋯ On the contrary, HIF-1α antisense oligonucleotide and siRNA were used to specifically downregulate HIF-1α expression, and then IF1 protein levels were significantly decreased in clone 9 cells. Meanwhile, downregulation of HIF-1α expression led to elevate the mitochondrial F(o)F₁-ATPase activity in the presence of Bis-Tris buffer (pH 6.5). In conclusion, these results suggested for the first time that the HIF-1 might play a crucial role in regulating IF1 protein expression in late septic liver.
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Remote ischemic preconditioning (RIPC) and local ischemic preconditioning (IPC) protect the myocardium from subsequent ischemia/reperfusion (I/R) injury. In this study, the protective effects of early RIPC, IPC, and the combination of both (RIPC-IPC) were characterized. Furthermore, the hypothesis was tested that protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs), important mediators of IPC, are activated in RIPC. ⋯ Remote ischemic preconditioning, IPC, and RIPC-IPC exert early protection against myocardial I/R injury. Remote ischemic preconditioning and local IPC exhibit different activation dynamics of signal transducers in the myocardium. The studied PKC-MAPK pathway is likely not involved in the protective effects of RIPC.