GUT LYMPH, PHOSPHOLIPIDS AND PMN Ca2+ ENTRY IN SHOCK

Univ Of Med/Dent Of Nj-Nj Medical School, Newark NJ

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Abstract

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