IMPAIRED GUT TRANSIT AND HYPERTONIC SALINE RESUSCITATION/PROJECT 3

肠梗阻是一种常见的问题，在需要积极的休克复苏的创伤患者中会导致不良后果。在休克的实验室模型中，持续性肠梗阻是由缺血/再灌注(I/R)诱导的促炎症反应引起的。标准的护理复苏，包括早期容量负荷乳酸盐林格氏和输血，旨在最大限度地减少休克侮辱的严重程度。然而，伴随着严重的震惊侮辱，标准的 CARE复苏会导致有问题的肠道水肿，而不是针对限制I/R诱导的促炎反应。事实上，这可能会使情况变得更糟。高渗盐水是一种有吸引力的替代方案，因为它需要相当大的TESS容量，而且最近的实验室研究表明，高渗盐水对休克所致的急性肺损伤具有抗炎保护作用。这个项目将解决这样的假设，即与标准的护理复苏相比，使用或不使用胶体的高渗盐水将通过不同地诱导局部抗炎而不是促炎，来减少肠系膜I/R后的肠道损伤和转运障碍。它将利用肠系膜上动脉闭塞的标准模型，该模型已被用于表征导致肠道损伤和肠道转运的I/R炎症。具体目标1将确定乳酸林格氏症中乳酸的D-异构体是否会引起严重的促炎反应，从而对肠道转运产生不利影响。特定目的2将确定高渗盐水复苏与其抗炎保护作用之间的剂量反应关系。特效靶3采用特效靶2中确定的高渗盐水的最佳抗炎剂量(S)来确定高渗盐水复苏及其抗炎作用和保护作用之间的时间关系。然后，通过证明当时间相关的炎症效应被阻断时，高渗盐水复苏的保护作用被取消，因果关系将得到证实。然后，具体目标4将确定胶体的添加是否改变了所观察到的高渗盐水复苏的抗炎效果。结合这些信息将有助于设计未来的肠道特定复苏策略，这些策略将最大限度地减少缺血，减少有问题的浮肿，并消除I/R炎症，以限制肠道损伤并加速其修复

Ileus is a common problem that contributes to adverse outcome in trauma patients who require aggressive shock resuscitation. In laboratory models of shock, persistent ileus is caused by ischemia/reperfusion (I/R) induced pro-inflammation. Standard of care resuscitation which involves early volume loading with lactated Ringer's and blood transfusions is directed at minimizing the severity of the shock insult. However, with severe shock insults, standard of care resuscitation causes problematic gut edema and is not directed at limiting I/R induced pro-inflammation. In fact, it may worsen it. Hypertonic saline is an attractive alternative because it requires considerable tess volume and recent laboratory studies have shown that hypertonic saline provides protective anti-inflammation against shock induced acute lung injury. This project will address the HYPOTHESIS that hypertonic saline, with or without a colloid compared to standard of care resuscitation, will decrease gut injury and impaired transit after mesenteric I/R by differentially inducing local anti-inflammation over pro-inflammation. It will utilize a standard model of superior mesenteric artery occlusion that has been used to characterize I/R inflammation that causes gut injury and impairs intestinal transit. Specific Aim 1 will determine whether the D-isomer of lactate in lactated Ringer's causes pro-inflammation significant enough to adversely effect intestinal transit. Specific Aim 2 will determine the dose response relationship between hypertonic saline resuscitation and its anti-inflammatory protective effects. Specific Aim 3 will use the optimal anti-inflammatory dose(s) of hypertonic saline identified in Specific Aim 2 to determine the temporal relationship between hypertonic saline resuscitation, its anti-inflammatory effects and its protective effects. Causal relationship will then be confirmed by demonstrating that when temporally related inflammatory effects are blocked, the protective effects of hypertonic saline resuscitation are abrogated. Specific Aim 4 will then determine if the addition of the colloid modifies the observed anti-inflammatory effects of hypertonic saline resuscitation. The combined information will help design future gut specific resuscitation strategies that will minimize ischemia, reduce problematic edema, and abrogate I/R inflammation to limit gut injury and hasten its repair