MECHANISMS OF CELL INJURY IN BURN COMPLICATED BY SEPSIS

描述(改编自申请者的摘要)：尽管有侵略性的液体 烧伤创伤、脓毒症患者的复苏及局部抗菌治疗 通常是由于真皮的丧失；从而导致败血症和结果 多器官衰竭是烧伤病房死亡的主要原因。研究来自 PI的实验室和其他人的研究表明，烧伤创伤和脓毒症 改变心循环功能，最近的研究表明，心肌 烧伤、创伤或脓毒症后的异常与细胞内有关 钙的积累导致随后的细胞损伤和功能障碍。 尽管这一领域已经迅速发展，但关于细胞的许多事情仍然未知 创伤或脓毒症后心脏功能障碍的潜在机制。这个 Pi的团队将他们的注意力集中在一种与临床相关的烧伤模型上 合并脓毒症的损伤(肺炎链球菌气管内给药 烧伤后24小时给药)，并显示出进行性心循环 在这个两次击打的模型中出现了功能障碍。具体目标1a将决定是否 烧伤/脓毒症加剧了在烧伤后出现的升高的[钙]和[Na2+] 单独烧伤，将确定改变的钠/钙离子对心脏的贡献 收缩功能障碍。具体目标1b将确定 一过性细胞酸中毒和H+/Na+交换改变为[Na2+]升高， 以及升高的[Na+]是否反过来促进[Ca2+]内的Na+/Ca2+交换 超载。具体目标2将确定烧伤的贡献/ 脓毒症引起的肌浆网钙离子转运(肌浆网钙流出、钙-ATPase)改变 活性、SERCA和肌浆网钙含量)对细胞内钙离子和心肌收缩的影响 烧伤/脓毒症所致肌丝钙离子的缺失和贡献 对心脏收缩功能障碍不敏感。特定目标研究3 将研究PKC激活在细胞内Na+/Ca~(2+)积累中的作用 烧伤脓毒症患者的心脏收缩功能障碍。特定目标的研究4 将确定增加的[Ca~(2+)]和活性氧物种的贡献 细胞凋亡在烧伤/脓毒症中的作用及进一步确定细胞凋亡的作用 烧伤/脓毒症引起的离子紊乱和心肌收缩 功能障碍。只有通过了解烧伤后所涉及的细胞事件 炎症性级联是否可以有适当的预防和治疗方式 旨在改善结果。

DESCRIPTION (adapted from applicant's abstract): Despite aggressive fluid resuscitation and topical antimicrobial therapy after burn trauma, sepsis frequently results from the loss of dermis; thus sepsis and resultant multiorgan failure are a major cause of death in the burn unit. Studies from the PI's lab and others' have shown that burn trauma and sepsis independently alter cardiocirculatory performance, and recent studies suggest that myocardial abnormalities after burn, trauma or sepsis are related to intracellular accumulation of calcium with subsequent cellular injury and dysfunction. Although this field has grown rapidly, much is still unknown about the cellular mechanisms underlying cardiac dysfunction after either trauma or sepsis. The PI's group have focused their attention on a clinically relevant model of burn injury complicated by sepsis (intratracheal administration of S. pneumoniae administered 24 hours postburn) and have shown progressive cardiocirculatory dysfunction in this two-hit model. Specific Aim 1a will determine if burn/sepsis exacerbates the increased [Ca2+] and [Na2+] shown to occur after burn alone and will determine the contribution of altered Na+/Ca2+ to cardiac contractile dysfunction. Specific aim 1b will determine the contribution of transient cellular acidosis and altered H+/Na+ exchange to increased [Na2+], and whether increased [Na+] in turn promotes Na+/Ca2+ exchange in [Ca2+] overload. Specific Aim 2 will determine the contribution of burn/ sepsis-mediated alterations in SR Ca2+ handling (SR Ca2+ efflux, Ca2+-ATPase activity, SERCA, and SR Ca content) to cellular Ca2+ and cardiac contractile deficits and determine the contribution of burn/sepsis induced myofilament Ca2+ insensitivity to cardiac contractile dysfunction. Studies in Specific Aim 3 will examine the role of PKC activation in intracellular Na+/Ca2+ accumulation and cardiac contractile dysfunction in burn sepsis. Studies in Specific Aim 4 will determine the contribution of increased [Ca2+] and reactive oxygen species to apoptosis in burn/sepsis and further determine the contribution of apoptosis to burn/sepsis-induced ionic derangements as well as cardiac contractile dysfunction. Only by understanding the cellular events involved in the postburn inflammatory cascade can adequate prevention and treatment modalities be designed to improve outcome.