MECHANISMS OF CELL INJURY IN BURN COMPLICATED BY SEPSIS

描述（由申请人提供）： 尽管在烧伤创伤的早期液体复苏、早期切除和移植以及使用局部和全身抗菌剂来控制伤口感染方面不断取得进展，但烧伤相关的真皮损失对烧伤患者的感染构成了重大风险。吸入性损伤、插管和长时间通气的需要导致肺炎的显著发生率，肺炎通常进展为多器官衰竭，这是一种死亡率为50%的综合征。一个持续的临床问题是，烧伤创伤后脓毒症的发展可能会加剧与初始损伤相关的炎症反应和器官功能障碍。许多研究描述了创伤和脓毒症中的心肌功能障碍，但确切的细胞机制仍不清楚。心肌抑制的一个共同特征是心肌细胞胞浆钙（[Ca 2 +]i）的积累。在之前的资助期间的时间过程研究证实，烧伤或脓毒症相关的心肌细胞Na+积累先于细胞Ca 2+的上升，这表明心肌细胞Na+积累可能是心肌细胞Ca 2+过载的先决条件。本文提出的研究将检查以下总体假设：心肌细胞的Na+积聚是烧伤创伤或脓毒症后的初始事件，并且通过PKC依赖性途径发生; Na+负荷反过来促进肌细胞Ca 2+负荷;由于特异性Ca 2+转运蛋白的表达和功能改变，Na ~+-Ca ~（2+）交换器和SERCA的改变可减少心肌细胞的Ca ~（2+）流出。线粒体和细胞核Ca 2+积累导致这些细胞器的损伤，产生自由基，改变DNA含量和完整性，心肌细胞凋亡和心肌功能障碍。我们进一步假设，烧伤或脓毒症相关的心肌损伤和功能障碍的恢复与DNA切除修复以及心肌细胞复制有关。拟议的工作集中在五个具体的目标，以增加我们的理解，烧伤和脓毒症相关的心肌损伤的细胞事件。

DESCRIPTION (provided by applicant): Despite continued improvements in early fluid resuscitation from burn trauma, early excision and grafting, and the use of both local and systemic antimicrobials to control wound infection, burn-related loss of the dermis poses a significant risk for infection in the burn patient. Inhalation injury, intubation and the need for prolonged ventilation contribute to a significant incidence of pneumonia that often progresses to multiple organ failure, a syndrome that carries a mortality rate of 50%. A persistent clinical concern is that the development of sepsis after burn trauma may exacerbate inflammatory responses and organ dysfunction associated with the initial injury. Numerous studies describe myocardial dysfunction in trauma and sepsis, but the precise cellular mechanisms remain unclear. One common feature of myocardial depression is the accumulation of cytosolic calcium ([Ca2+]i) by cardiomyocytes. Time course studies during the previous funding period confirmed that burn- or sepsis-related myocyte accumulation of Na+ precedes the rise in cellular Ca2+, suggesting that cardiomyocyte accumulation of Na+ may be a prerequisite for myocyte Ca2+ overload. The studies proposed herein will examine the overall hypothesis that Na+ accumulation by the cardiomyocytes is an initial event after burn trauma or sepsis and occurs via a PKC dependent pathway; Na+ loading, in turn, promotes myocyte Ca2+ loading; myocyte Ca2+ dyshomeostasis persists due to altered expression and function of specific Ca2+ transport proteins, i.e., alterations in Na+-Ca2+ exchanger and SERCA may decrease Ca2+ efflux from the myocytes. Mitochondrial and nuclear Ca2+ accumulation contribute to injury of these cellular organelles, producing free radical generation, altered DNA content and integrity, myocyte apoptosis and myocardial dysfunction. We further hypothesize that recovery from burn or sepsis-related myocardial injury and dysfunction is related to DNA excisional repair as well as myocyte replication. The proposed work focuses on five specific aims to increase our understanding of the cellular events involved in burn and sepsis-related myocardial injury.