Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Time-Dependent and Organ-Specific Changes in Mitochondrial Function, Mitochondrial DNA Integrity, Oxidative Stress and Mononuclear Cell Infiltration in a Mouse Model of Burn Injury.

Severe thermal injury induces a pathophysiological response that affects most of the organs within the body; liver, heart, lung, skeletal muscle among others, with inflammation and hyper-metabolism as a hallmark of the post-burn damage. Oxidative stress has been implicated as a key component in development of inflammatory and metabolic responses induced by burn. The goal of the current study was to evaluate several critical mitochondrial functions in a mouse model of severe burn injury. Mitochondrial bioenergetics, measured by Extracellular Flux Analyzer, showed a time dependent, post-burn decrease in basal respiration and ATP-turnover but enhanced maximal respiratory capacity in mitochondria isolated from the liver and lung of animals subjected to burn injury. Moreover, we detected a tissue-specific degree of DNA damage, particularly of the mitochondrial DNA, with the most profound effect detected in lungs and hearts of mice subjected to burn injury. Increased mitochondrial biogenesis in lung tissue in response to burn injury was also observed. Burn injury also induced time dependent increases in oxidative stress (measured by amount of malondialdehyde) and neutrophil infiltration (measured by myeloperoxidase activity), particularly in lung and heart. Tissue mononuclear cell infiltration was also confirmed by immunohistochemistry. The amount of poly(ADP-ribose) polymers decreased in the liver, but increased in the heart in later time points after burn. All of these biochemical changes were also associated with histological alterations in all three organs studied. Finally, we detected a significant increase in mitochondrial DNA fragments circulating in the blood immediately post-burn. There was no evidence of systemic bacteremia, or the presence of bacterial DNA fragments at any time after burn injury. The majority of the measured parameters demonstrated a sustained elevation even at 20-40 days post injury suggesting a long-lasting effect of thermal injury on organ function. The current data show that there are marked time-dependent and tissue-specific alterations in mitochondrial function induced by thermal injury, and suggest that mitochondria-specific damage is one of the earliest responses to burn injury. Mitochondria may be potential therapeutic targets in the future experimental therapy of burns

Changes in mitochondrial volume in response to burn injury.

<p>Mitochondrial biogenesis was assayed using specific activity of citrate synthase in extract isolated from <b>(A)</b> liver, <b>(B)</b> lungs and <b>(C)</b> heart of mice subjected to burn injury. The results are based on n = 6 per group and represent mean±SD. ** p<0.01, relatively to sham animals.</p

Changes in circulating total and mitochondrial DNA in response to burn injury.

<p>The amount of <b>(A)</b> total DNA and <b>(B)</b> mitochondrial DNA fragments in plasma of mice subjected to burn injury was analyzed using qPCR. The results are based on n = 6 per group and represent mean±SD. *, ** p<0.05 and p<0.01 respectively, relatively to sham treated animals.</p

Changes in histopathology of liver induced by burn.

<p>Liver sections of animals at 1 and 4 days post burn injury with there control shams were stained with (<b>A</b>) H&E; (<b>B</b>) MPO; (<b>C</b>) CD68; (<b>D</b>) neutrophil elastase. Representative pictures of n = 4 for each animal group are shown.</p

Changes in mitochondrial and nuclear DNA integrity in response to burn injury.

<p>Damage to nuclear and mitochondrial DNA was quantified using LA-PCR assay in <b>(A)</b> liver, <b>(B)</b> lungs and <b>(C)</b> heart of mice subjected to burn injury. The results are based on n = 6 per group and represent mean±SD. *, ** p<0.05 and p<0.01 respectively, relatively to sham animals.</p

Burn injury induces time-dependent changes in the mitochondrial bioenergetics in the lung.

<p>Bioenergetic parameters of the isolated mitochondria from lungs of mice subjected to burn injury were analyzed by Extracellular Flux Analysis. <b>(A)</b> Traces of oxygen consumption of mitochondria isolated from sham or burn injured animals at various time points post burn injury are shown. <b>(B)</b> Calculated bioenergetics parameters are shown. The results are based on n = 6 per group and represent mean±SD. *, ** p<0.05 and p<0.01 respectively, relative to sham animals.</p

Changes in MDA, an index of lipid peroxidation, in response to burn injury.

<p>MDA levels were measured in <b>(A)</b> liver, <b>(B)</b> lungs and <b>(C)</b> heart of mice subjected to burn injury. The results are based on n = 6 per group and represent mean±SD. *, ** p<0.05 and p<0.01 respectively, relatively to sham animals.</p

Changes in various parameters in various organs after burn injury.

<p>A single arrow shows a statistically significant change; double arrows show statistically significant changes that are more than 100% increases (i.e. doubling of the parameter) or a more than 50% decrease in the given parameter. Horizontal arrows indicate no significant change in the parameter.</p