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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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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The role of the Toll-like receptor 4 (TLR4), a component of the innate immune system, in the development of burn-induced acute lung injury (ALI) has not been completely defined. Recent data suggested that an intact TLR4 plays a major role in the development of organ injury in sterile inflammation. We hypothesized that burn-induced ALI is a TLR4-dependent process. ⋯ Burn-induced ALI develops within 24 h after the initial thermal insult in our model. Toll-like receptor 4 KO animals were clearly protected and had a much less severe lung injury. Our data suggest that burn-induced ALI is a TLR4-dependent process.
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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.