GUT LYMPH, PHOSPHOLIPIDS AND PMN Ca2+ ENTRY IN SHOCK

点击翻译按钮获取中文摘要

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.