MECHANISMS OF CELL INJURY IN BURN COMPLICATED BY SEPSIS

烧伤并发败血症的细胞损伤机制

• 批准号: 6386820
• 负责人: JURETA W HORTON
• 金额: $ 28.86万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6386820
• 关键词: Streptococcus pneumoniae; apoptosis; bacteria infection mechanism; bacterial cytopathogenic effect; burns; calcium flux; disease /disorder model; free radical oxygen; heart contraction; intracellular transport; laboratory rat; medical complication; myocardium disorder; protein kinase C; sarcoplasmic reticulum; sodium ion; trauma

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.

描述（改编自申请人的摘要）：尽管有腐蚀性液体 烧伤、败血症后的复苏和局部抗菌治疗 常常是由于真皮缺失造成的；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。研究来自 PI 的实验室和其他人的实验室已经证明烧伤和败血症是独立的 改变心脏循环性能，最近的研究表明心肌 烧伤、创伤或败血症后的异常与细胞内 钙的积累导致随后的细胞损伤和功能障碍。 尽管这一领域发展迅速，但关于蜂窝技术仍然有很多未知之处。 创伤或败血症后心脏功能障碍的机制。这 PI 的团队将注意力集中在临床相关的烧伤模型上 损伤并发脓毒症（气管内注射肺炎链球菌） 烧伤后 24 小时给药）并显示出渐进的心脏循环 这种两次打击模型中的功能障碍。具体目标 1a 将确定是否 烧伤/脓毒症会加剧 [Ca2+] 和 [Na2+] 的增加， 单独燃烧，将确定改变的 Na+/Ca2+ 对心脏的贡献 收缩功能障碍。具体目标 1b 将决定以下贡献： 短暂的细胞酸中毒和 H+/Na+ 交换改变导致 [Na2+] 增加， [Na+] 的增加是否会反过来促进 [Ca2+] 中 Na+/Ca2+ 的交换 超载。具体目标 2 将确定燃烧/的贡献 脓毒症介导的 SR Ca2+ 处理改变（SR Ca2+ 流出、Ca2+-ATPase 活性、SERCA 和 SR Ca 含量）对细胞 Ca2+ 和心脏收缩的影响 缺陷并确定烧伤/脓毒症引起的肌丝 Ca2+ 的贡献 对心脏收缩功能不敏感。具体目标研究 3 将检查 PKC 激活在细胞内 Na+/Ca2+ 积累中的作用 和烧伤脓毒症中的心脏收缩功能障碍。具体目标研究 4 将确定增加的 [Ca2+] 和活性氧的贡献 烧伤/脓毒症中细胞凋亡的影响，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。只有了解烧伤后涉及的细胞事件 炎症级联反应是否可以采取适当的预防和治疗方式 旨在改善结果。