MECHANISMS OF CELL INJURY IN BURN COMPLICATED BY SEPSIS

描述（改编自申请人摘要）：尽管有侵蚀性液体 烧伤、脓毒症复苏与局部抗菌治疗 通常由真皮的损失引起;因此败血症和由此产生的 多器官衰竭是烧伤科死亡的主要原因。研究从 PI实验室和其他实验室已经表明，烧伤创伤和脓毒症 改变心循环性能，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 钙的积累伴随着随后的细胞损伤和功能障碍。 尽管这一领域发展迅速，但关于细胞生物学的许多知识仍然是未知的。 创伤或脓毒症后心功能不全的潜在机制。的 PI的小组将注意力集中在临床相关的烧伤模型上 损伤并发脓毒症（S.肺炎 烧伤后24小时给药），并显示出进行性心循环 在这个两次打击的模型中的功能障碍。具体目标1a将确定是否 烧伤/脓毒症加剧了[Ca 2 +]和[Na 2 +]的增加， 并将确定改变的Na+/Ca 2+对心脏的贡献。 收缩功能障碍具体目标1b将决定 短暂的细胞酸中毒和改变的H+/Na+交换增加[Na 2 +]， 以及[Na+]增加是否反过来促进[Ca 2 +]中的Na+/Ca 2+交换 超载。具体目标2将确定燃烧/ 脓毒症介导的SR Ca 2+处理（SR Ca 2+流出，Ca 2 +-ATP酶）的改变 活性、SERCA和SR Ca含量）对细胞Ca 2+和心肌收缩的影响 缺陷和确定烧伤/脓毒症诱导的肌丝Ca 2+的贡献 对心脏收缩功能障碍不敏感。研究具体目标3 将研究PKC激活在细胞内Na+/Ca 2+积累中的作用 和心脏收缩功能障碍。具体目标4 将决定增加的[Ca 2 +]和活性氧的贡献 烧伤/脓毒症中的细胞凋亡，并进一步确定细胞凋亡的贡献 烧伤/脓毒症引起的离子紊乱以及心脏收缩 功能障碍只有了解烧伤后的细胞活动 炎性级联反应可以适当预防和治疗方式， 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.