Extracellular histones are a target in myocardial ischaemia reperfusion injury

Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins (DAMPs) in sepsis. Aims The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction. Methods and results Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralising compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS, or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size. Conclusion Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium. Translational perspective Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). New approaches are needed to prevent cardiomyocyte injury and limit final infarct size. We show that histones released from damaged cells, and histone-H4 in particular, causes rapid cardiomyocyte death during I/R. mCBS, a compounds targeting histones non-specifically, was cardioprotective in ex vivo rat hearts, while HIPe, a targeting histone H4 specifically, was cardioprotective in an in vivo rat model. HIPe may have potential as a therapeutic agent in the setting of acute myocardial infarction.

Compartment syndrome of the hand following iatrogenic intra-arterial administration of epinephrine during cardiopulmonary resuscitation

A 26-year-old woman developed acute compartment syndrome (ACS) of her right hand secondary to reperfusion syndrome. She suffered an out-of-hospital cardiac arrest following a pregabalin overdose. Attending paramedics mistakenly gave intra-arterial epinephrine into her right brachial artery. On resolution of her brachial artery spasm, she developed a reperfusion injury to her right hand and subsequently ACS. A four-incision fasciotomy with carpal tunnel decompression was performed and was successful in reversing focal ischaemia and an irreversible functional deficit. This case demonstrates an unusual case of hand ACS secondary to temporary limb ischaemia and reperfusion syndrome following iatrogenic intra-arterial epinephrine administration. We also summarise the current available literature on ACS of the hand including the aetiology, treatment and use of an intracompartmental monitor.

Electroacupuncture Pre-treatment Exerts an Anti-apoptotic Effect in Cerebral Ischaemia and Reperfusion Injury in Rats

Background: Electroacupuncture (EA) pre-treatment can play a significant neuroprotective role in rats with cerebral ischaemia and reperfusion (CIR) injury, but the specific mechanism needs to be further elucidated. <br><br>Objective: To investigate the effects of EA pre-treatment on apoptosis-related proteins Bax, Bcl-2, Cytochrome c (cyt c), cleaved caspase-9 and -3 in rats with CIR injury. Methods: CIR injury was induced using middle cerebral artery occlusion (MCAO) ischaemia-reperfusion. Thirty-six male Specific Pathogen Free (SPF) Sprague-Dawley rats were randomly divided into three groups: Sham (n=12), MCAO (n=12), and the EA+MCAO group (n=12). EA+MCAO group rats received electroacupuncture at DU20 for 2 consecutive weeks before MCAO model preparation. After 24 h of reperfusion, neurological deficits were evaluated by modified neurological severity scores. Brain infarct volumes were examined by 2,3,5-triphenyltetrazolium chloride staining. Expression of Bax, Bcl-2, cyt c, cleaved caspase-9 and -3 in the ischaemic penumbra were detected by Western blotting, and apoptosis evaluated by TUNEL staining. <br><br>Results: After perfusion for 24 h, compared with the MCAO group, the neurological deficit scores and brain infarct volumes in the EA+MCAO group were significantly decreased (P<0.05), as was the level of Bax (P<0.05) or the Bax/Bcl-2 ratio (P<0.05), levels of cyt c, cleaved caspase-9 and -3 also decreased (P<0.05), like the number of TUNEL-positive cells (P<0.05), in contrast, the level of Bcl-2 increased (P<0.05). <br><br>Conclusion: EA pre-treatment exerts an anti-apoptotic effect through Bax-to-Bcl-2 ratio downregulation, blockage of mitochondrial cyt c release to the cytosol, and reduction of caspase-9 and -3 expression in rats with CIR injury.

Corticomedullary Shunting After Ischaemia and Reperfusion in The Porcine Kidney?

Background: An animal model offers the opportunity to study organs in vivo and the porcine model was chosen to simulate a renal transplantation with complications. Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this matter. We studied renal perfusion after renal ischaemia and reperfusion.Methods: Renal perfusion distribution was examined by use of 153Gadolinium-labeled microspheres (MS) after 2 hours (hrs) and 4 hrs ischaemia of the pig kidney followed by 4 hrs of reperfusion. Intra-arterial injected MS are trapped in the glomeruli in renal cortex, which means that MS are not present in the medulla under normal physiological conditions.Results: Visual evaluation after reperfusion demonstrated that MS redistributed from the renal cortex to the medulla in 6 out of 16 pigs (38%) subjected to 4 hrs ischaemia and in one out of 18 pigs subjected to 2 hrs ischaemia. Central renal uptake of MS covering the medullary/total renal uptake was significantly higher in kidneys subjected to 4 hrs ischaemia compared with pigs subjected to 2 hrs ischaemia (69±5% vs. 63±1%, p<0.001), and also significantly higher than in the contralateral kidney (69±5% vs. 63±2, p<0.001). Analysis of blood and urine demonstrated no presence of radioactivity. Conclusion: The study demonstrated the presence of MS in the renal medulla in response to renal ischaemia and reperfusion suggesting that severe ischaemia and reperfusion of the pig kidney leads to opening of functional shunts bypassing glomeruli.

Monitoring the skin NADH changes during ischaemia and reperfusion in humans

Nicotinamide adenine dinucleotide (NADH/NAD+) is involved in many important biochemical reactions in human metabolism, including participation in energy production by mitochondria. Flow Mediated Skin Fluorescence (FMSF) is a non-invasive method to study dynamic changes in the content of the reduced form of NADH by measuring the optical properties of NADH related to the emission of the autofluorescent light (460 nm) after an earlier excitation by ultraviolet light. This review summarises the available studies using this method to describe its potential and limitations.