CARDIAC RESPONSES TO THERMAL INJURY

该实验室之前的研究表明，心脏 严重烧伤后的收缩功能障碍，尽管有侵入性液体 复苏。失败者目前的肌力支持方案 心脏功能不全通常是由于烧伤引起的心脏β-受体的改变。 肾上腺素能受体功能与心脏钙转运的改变 肌浆网，提示烧伤后的亚细胞基础 心功能障碍是烧伤引起的钙可利用性改变 对心肌收缩蛋白的影响。最近的研究表明 提示中性粒细胞衍生的氧自由基(OFR)损伤 肌膜和亚细胞膜与烧伤后心脏的关系 收缩赤字。这项研究的目标是检查系统性的 以及烧伤改变的局部细胞和生化机制 心脏收缩功能。这项提议将检验这一假说 急性热损伤会引发全身缺血/再灌注， 导致肠粘膜功能障碍，肠道屏障丧失 炎症介质的功能和释放，从而启动全身 炎症反应，与当地因素共同导致 心肌细胞收缩功能严重受损。为了澄清 导致烧伤后心脏功能障碍的局部心脏因素， 从假烧伤、烧伤后分离心肌细胞和中性粒细胞 动物，以及烧伤前中性粒细胞耗尽的动物；心肌细胞 收缩功能(缩短率)与细胞内离子钙离子 浓度(使用荧光钙指示剂Fura-2测量) 将被用来检测中性粒细胞对钙的贡献 失稳与烧伤后心肌细胞收缩功能。此外，我们 将确定烧伤后心脏疾病的一个潜在机制 收缩功能障碍包括烧伤引起的cAMP减少 制作。此外，这项研究还将考察 中性粒细胞(及其细胞毒产物)和细胞因子对冠状动脉的影响 血管内皮细胞功能及检测冠脉内皮细胞的作用 心肌细胞收缩功能的损伤和功能障碍。最后，这一点 提案将阐明中性粒细胞衍生的氧自由基诱导的作用 内脏血管收缩并导致肠屏障丧失 对全身细胞因子释放和心脏收缩功能障碍的作用。 这些研究将检验中性粒细胞作为常见的 分母对肠道屏障功能和肠粘膜损伤的影响 心肌细胞。这项提案的长期目标是设计 基于对实验动物的研究的治疗策略以减轻或 预防急性烫伤后心功能不全。

Previous work from this laboratory has shown significant cardiac contractile dysfunction after a major burn injury despite aggressive fluid resuscitation. Current regimens of inotropic support for the failing heart are often inadequate due to burn-mediated changes in cardiac beta- adrenergic receptor function and altered calcium transport by the cardiac sarcoplasmic reticulum, suggesting that the subcellular basis for postburn cardiac dysfunction is burn-mediated alterations in calcium availability to the myocardial contractile proteins. More recent studies have suggested that neutrophil-derived oxygen free radicals (OFR) damage sarcolemma and subcellular membranes, contributing to postburn cardiac contractile deficits. The goal of this study is to examine the systemic and local cellular and biochemical mechanisms by which burn injury alters cardiac contractile function. This proposal will examine the hypothesis that acute thermal injury initiates systemic ischemia/reperfusion, resulting in intestinal mucosal dysfunction, a loss of gut barrier function, and release of inflammatory mediators which initiate a systemic inflammatory response, which, in concert with local factors lead to profound impairment of myocyte contractile function. To elucidate the local cardiac factors which contribute to postburn cardiac dysfunction, myocytes and neutrophils with be isolated from sham burned, burned animals, as well as from preburn neutrophil depleted animals; myocyte contractile function (velocity of shortening) and intracellular ionic Ca2+ concentrations (measured using the fluorescent calcium indicator, fura-2) will be used to examine the contribution of neutrophils to calcium dyshomeostasis and postburn myocyte contractile function. In addition, we will determine whether one mechanism underlying postburn cardiac contractile dysfunction includes burn-mediated attenuation of cAMP production. In addition, this study will examine the contribution of the neutrophils (and their cytotoxic products) and cytokines on coronary endothelial function and examine the effects of coronary endothelial injury and dysfunction on myocyte contractile function. Finally, this proposal will elucidate the role of neutrophil derived OFR-induced splanchnic vasoconstriction with resultant loss of intestinal barrier function to systemic cytokine release and cardiac contractile dysfunction. These studies will examine the role of the neutrophil as the common denominator initiating injury to intestinal barrier function and to the cardiac myocyte. The long term goal of this proposal is to design treatment strategies based on studies in experimental animals to lessen or prevent cardiac dysfunction after acute thermal injury.