GUT LYMPH, PHOSPHOLIPIDS AND PMN Ca2+ ENTRY IN SHOCK

创伤是1至45岁之间死亡的主要原因。1至36岁之间，死亡 超过了所有其他死因的总和美国每年有5万名受害者 创伤早期死亡，大多数死于创伤和失血性休克（T/HS）触发全身性休克。 炎症反应综合征（SIRS）。休克导致SIRS时，低流量继之以再灌注损伤 肠道，引起炎症介质的合成，然后炎症介质可以通过 肠道扩张 中性粒细胞（PMN）是损伤早期免疫应答的关键效应细胞。他们是关键的参与者 无论是器官衰竭还是对感染的反应中性粒细胞容易被肠淋巴和其他 炎症刺激，但是SIRS中的PMN功能障碍可以临床上表现为过度活化和器官损伤。 衰竭或功能减退和败血症。因此，暴露于T/HS淋巴液后的异常PMN反应是导致T/HS淋巴液损伤的主要原因。 公共卫生问题，但它们是复杂的和不完全的特点。我们最近的研究表明，PMN 介导的炎症受到钙进入细胞的关键调节， 称为钙库操作的钙进入（SOCE）。我们还表明，SOCE反过来又受一类 分子称为溶血磷脂（LPL）。初步数据表明，中性粒细胞对LPL的反应， 在创伤免疫并发症中发挥关键作用，中性粒细胞对LPL的反应受到T/HS的强烈调节， 阻断LPL的合成或钙动员作用可减少PMN的活化， 防止休克后器官衰竭 因此，该提案旨在确定肠道淋巴介导的全身炎症如何改变 PMN中LPL信号传导，这种信号传导修饰如何影响PMN功能，以及LPL的抑制是否 合成或LPL依赖的SOCE可以阻止T/HS肠淋巴的病理性PMN反应， 容易导致器官损伤和败血症此外，由于T/HS后PMN功能的改变， 通常性别特异性，我们将确定哪些方面的肠道淋巴相关的LPL信号功能障碍，在中性粒细胞 取决于性别和荷尔蒙环境这些信息将帮助我们以后优化LPL和SOCE的使用 在特定的创伤人群中抑制。

Trauma is the leading cause of death between the ages of 1 and 45. Between the ages of 1 and 36, death from trauma exceeds all other causes of death combined. Of the 50,000 victims per year in the USA who survive trauma early on only to die later, most die when trauma and hemorrhagic shock (T/HS) trigger the Systemic Inflammatory Response Syndrome (SIRS). Shock leads to SIRS when low-flow followed by reperfusion injures the gut, causing the synthesis of inflammatory mediators which can then enter the systemic circulation via intestinal lymphatics. Neutrophils (PMN) are key effector cells in early immune responses to injury. They are critical participants both in organ failure and in responses to infection. PMN are susceptible to activation by gut lymph and other inflammatory stimuli, yet PMN dysfunction in SIRS can be clinically manifest either as hyper-activation and organ failure or as hypo-function and sepsis. Thus aberrant PMN responses after exposure to T/HS lymph are a major public health problem, but they are complex and incompletely characterized. Our recent work suggests that PMN mediated inflammation is critically regulated by entry of calcium into the cell which is dependent on a process called Store-Operated Calcium Entry (SOCE). We have also shown that SOCE in turn, is regulated by a class of molecules called the lysophospholipids (LPL). Preliminary data suggests that PMN responses to LPL play a critical role in the immune complications of trauma, that PMN responses to LPL are strongly regulated by T/HS, and that blocking either the synthesis or the calcium mobilizing effects of LPL diminishes PMN activation and prevents organ failure after shock. This proposal therefore seeks to determine how gut lymph-mediated systemic inflammation modifies LPL signaling in PMN, how such signaling modification may affect PMN function, and whether inhibition of LPL synthesis or LPL-dependent SOCE can prevent the pathologic PMN responses to T/HS gut lymph which predispose to organ injury and sepsis. In addition, since alterations in PMN function subsequent to T/HS are often gender specific, we will determine which aspects of gut lymph-related LPL signal dysfunction in the PMN depend upon gender and hormonal milieu. This information will help us later to optimize use of LPL and SOCE inhibition in specific trauma populations.