Szczesny Bartosz, Brunyánszki Attila, Ahmad Akbar, Oláh Gabor, Porter Craig, Toliver-Kinsky Tracy, Sidossis Labros, Herndon David N, Szabo Csaba
Department of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, United States of America.
Shriners Hospitals for Children, Galveston, TX, United States of America.
PLoS One. 2015 Dec 2;10(12):e0143730. doi: 10.1371/journal.pone.0143730. eCollection 2015.
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.
严重热损伤会引发一种病理生理反应，影响体内大多数器官，如肝脏、心脏、肺、骨骼肌等，炎症和高代谢是烧伤后损伤的标志。氧化应激被认为是烧伤诱导的炎症和代谢反应发展的关键因素。本研究的目的是评估严重烧伤小鼠模型中的几种关键线粒体功能。通过细胞外通量分析仪测量的线粒体生物能量学显示，烧伤后，从烧伤动物的肝脏和肺中分离出的线粒体的基础呼吸和ATP周转率随时间下降，但最大呼吸能力增强。此外，我们检测到了组织特异性的DNA损伤程度，尤其是线粒体DNA的损伤，在烧伤小鼠的肺和心脏中检测到的影响最为显著。还观察到肺组织中因烧伤而导致的线粒体生物发生增加。烧伤还会导致氧化应激（通过丙二醛含量测量）和中性粒细胞浸润（通过髓过氧化物酶活性测量）随时间增加，尤其是在肺和心脏中。免疫组织化学也证实了组织单核细胞浸润。烧伤后，肝脏中聚（ADP - 核糖）聚合物的数量减少，但在后期心脏中增加。所有这些生化变化也与所研究的所有三个器官的组织学改变有关。最后，我们在烧伤后立即检测到血液中线粒体DNA片段显著增加。没有证据表明存在全身性菌血症，或烧伤后任何时间存在细菌DNA片段。即使在受伤后20 - 40天，大多数测量参数仍持续升高，表明热损伤对器官功能有长期影响。目前的数据表明，热损伤诱导的线粒体功能存在明显的时间依赖性和组织特异性改变，并表明线粒体特异性损伤是烧伤损伤的最早反应之一。线粒体可能是未来烧伤实验治疗中的潜在治疗靶点。
