GUT LYMPH, PHOSPHOLIPIDS AND PMN Ca2+ ENTRY IN SHOCK

创伤是1至45岁儿童的主要死亡原因。在1岁到36岁之间，死亡 创伤造成的死亡超过了所有其他死因的总和。在美国每年幸存的50,000名受害者中 创伤早期只是后来死亡，大多数人死于创伤和失血性休克(T/HS)触发的全身性 炎症反应综合征(SIRS)低流量再灌注损伤时休克导致全身炎症反应综合征 肠道，导致炎性介质的合成，然后可以通过 肠道淋巴管。 中性粒细胞(PMN)是损伤早期免疫反应中的关键效应细胞。他们是关键的参与者 在器官衰竭和对感染的反应中都是如此。中性粒细胞容易被肠道淋巴和其他物质激活 炎症刺激，但SIRS的PMN功能障碍在临床上既可以表现为过度激活，也可以表现为器官 衰竭或表现为功能减退和败血症。因此，暴露于T/HS淋巴后的PMN异常反应是一个主要的 公共卫生问题，但它们是复杂的和不完全的特征。我们最近的研究表明，PMN 调节炎症的关键是钙离子进入细胞，这依赖于一个过程。 称为商店操作的钙输入(SOCE)。我们还表明，SOCE反过来又受一类 被称为溶血磷脂(LPL)的分子。初步数据显示，PMN对LPL的反应起到了 在创伤的免疫并发症中起关键作用，PMN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降低PMN的活化和 防止休克后的器官衰竭。 因此，这个建议试图确定肠道淋巴介导的全身炎症是如何改变的。 LPL在PMN中的信号转导，这种信号改变可能如何影响PMN的功能，以及LPL是否被抑制 合成或LPL依赖的SOCE可阻止T/HS肠淋巴对PMN的病理性反应 易发生器官损伤和败血症。此外，由于在T/HS之后PMN功能的改变是 通常，我们将确定PMN中与肠道淋巴相关的LPL信号功能障碍的哪些方面 取决于性别和荷尔蒙环境。这些信息将在以后帮助我们优化LPL和SOCE的使用 在特定创伤人群中的抑制作用。

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.