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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Tissue-specific circulating micro-RNAs (miRNAs) are released into the blood after organ injury. In an ischemic porcine cardiogenic shock model, we investigated the release pattern of cardiac-specific miR-208b and liver-specific miR-122 and assessed the effect of therapeutic hypothermia on their respective plasma levels. Pigs were anesthetized, and cardiogenic shock was induced by inflation of a percutaneous coronary intervention balloon in the proximal left anterior descending artery for 40 min followed by reperfusion. ⋯ Therapeutic hypothermia significantly diminished the increase in miR-122 compared with the normothermic group (P < 0.005). In our model, hypothermia was initiated after coronary reperfusion and did not affect either myocardial damage as previously assessed by magnetic resonance imaging or the plasma level of miR-208b. Our results indicate that liver-specific miR-122 is released into the circulation in the setting of cardiogenic shock and that therapeutic hypothermia significantly reduces the levels of miR-122.
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The peroxisome proliferator-activated receptor α (PPAR-α) is a member of the nuclear receptor family with many important physiologic roles related to metabolism and inflammation. Previous research in pediatric patients with septic shock revealed that genes corresponding to the PPAR-α signaling pathway are significantly downregulated in a subgroup of children with more severe disease. In this study, PPAR-α expression analysis using whole-blood derived RNA revealed that PPAR-α expression was decreased in patients with septic shock and that the magnitude of that decrement correlated with the severity of disease. ⋯ Plasma cytokine analysis demonstrated decreased levels of interleukin 1β (IL-1β), IL-6, IL-17, keratinocyte-derived cytokine, macrophage chemoattractant protein 1, macrophage inflammatory protein 2, and tumor necrosis factor α at 24 h in PPAR-α knockout animals. Cell surface markers of activation on splenic dendritic cells, macrophages, and CD8 T cells were reduced in PPAR-α null animals, and the bacterial load in lung and splenic tissues was increased. These data indicate that reduced or absent PPAR-α expression confers a survival disadvantage in sepsis and that PPAR-α plays a role in maintaining appropriate immune functions during the sepsis response.
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Excessive endoplasmic reticulum stress (ERS) disrupts protein translation, protein folding, and calcium homeostasis and may contribute to ischemia-reperfusion injury. Saponins extracted from the stems and leaves of Panax quinquefolium (PQS) protect rat myocardium against ischemia-reperfusion injury, but it is not known if suppression of ERS contributes to cardioprotection. Neonatal rat cardiomyocytes were subjected to hypoxia-reoxygenation (H-R) in the presence of PQS or vehicle. ⋯ We confirmed that PQS protects cardiomyocytes from H-R-induced injury and apoptotic cell death. Furthermore, PQS suppressed H-R-induced excessive ERS, as evidenced by reduced caspase 12 activation and decreased glucose-regulated protein 78, calreticulin, and CCAAT/enhancer-binding protein homologous protein overexpression. These results indicated that PQS could alleviate H-R injury of cardiomyocytes, which would be probably related to inhibiting excessive ERS induced by H-R.
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Cardiac cycle is regulated by a complex interplay between autonomic nervous system and cardiac pacemaker cells. Decreased heart rate variability (HRV) and increased cardiac rhythm regularity are associated with poor prognosis in patients with systemic inflammation (e.g., sepsis). However, the underlying mechanism of decreased HRV in systemic inflammation is not understood. ⋯ The chronotropic responsiveness to adrenergic stimulation was identical in controls and endotoxin-treated rats. These data propose that systemic inflammation is linked to reduced cardiac responsiveness to cholinergic stimulation. This may lead to partial uncoupling of cardiac pacemaker cells from autonomic neural control and can explain decreased HRV during systemic inflammation.
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Lipocalin-2 (LCN-2) is a 25-kDa secretory protein currently used as a biomarker for renal injury and inflammation. Its source and cause of the increased serum levels are unclear. The current study compares LCN-2 gene expression with known major acute-phase proteins in the liver in a rat and mouse model of turpentine oil-induced sterile abscess. ⋯ Lipocalin-2 is the major acute-phase protein in rat as compared with α₂-macroglobulin and hemoxygenase 1 and comparable with serum amyloid A in mouse whose gene expression is mainly controlled by interleukin 6. The liver is the main source of serum LCN-2 in the case of APR. ABBREVIATIONS-LCN-2-lipocalin-2-α₂M-α₂-macroglobulin-HO-1-hemoxygenase 1-IL-6-interleukin 6-SAA-serum amyloid A-TO-turpentine oil-APR-acute-phase reaction.