Short-term mesenteric lymphatic adaptation to trauma-related intestinal edema

创伤患者急救复苏后发病率和死亡率的一个主要因素是肠道间质水肿形成所引起的肠道功能障碍。肠系膜淋巴系统通过将间质液体回流到血液中，在限制肠水肿方面起着至关重要的作用。虽然淋巴转运被认为是消除水肿的主要机制，但我们最近发现，淋巴转运由两个非常不同的过程控制。当间质压力超过中心静脉压力时，淋巴管可以充当管道血管，被动地将淋巴输送到压力梯度下。 然而，因为淋巴管是肌肉的，并且周期性收缩，它们可以充当泵，积极地将淋巴从通常的低压力间质空间向上输送到压力较高的静脉。我们的初步数据表明，现有血管中的淋巴肌肉在三天内对淋巴流量的变化做出了功能适应。这一短期适应期与创伤患者管理的关键时期密切相关。这些适应性变化的相关分子途径和功能后果目前尚不清楚。这项研究的中心假设是，肠系膜淋巴管将通过成为更好的管道来适应肠系膜静脉高压和肠水肿，并将通过成为更好的泵来适应下游淋巴阻塞。我们将通过追求两个具体目标来检验这一假设。 1.定量研究肠系膜静脉高压引起的淋巴流量增加对肠系膜淋巴管收缩功能、生物力学、钙敏感性及基因和蛋白表达的影响。 2.定量研究部分下游淋巴管阻塞引起的淋巴流量减少对肠系膜淋巴管收缩功能及基因和蛋白表达的影响。 我们将使用两种牛模型，肠系膜静脉高压和肠系膜淋巴阻塞，以探讨淋巴适应性。这项研究工作有望确定淋巴肌肉适应与器官水肿形成相关的改变的水动力条件的分子途径和分子表达的关键变化。此外，它还将量化这种适应的功能和生物力学后果。这些信息将指导开发新的药物或分子治疗措施，旨在加强淋巴对水肿液的清除，并减少该治疗所需的时间和费用。

A major contributor to morbidity and mortality in trauma patients following emergency resuscitation is intestinal dysfunction caused by interstitial edema formation in the bowel. The mesenteric lymphatic system plays a crucial role in limiting bowel edema by returning interstitial fluid to the blood stream. Although lymph transport is recognized as the primary mechanism for edema resolution, we have recently identified that lymph transport is governed by two very different processes. When interstitial pressure exceeds central venous pressure, lymphatic vessels can act as conduit vessels, passively transporting lymph down a pressure gradient. However, because lymphatic vessels are muscular and cyclically contract, they can act as pumps, actively transporting lymph up a pressure gradient from the normally low-pressure interstitial space to the higher-pressure veins. Our preliminary data indicate that lymphatic muscle in existing vessels undergoes functional adaptation in response to changes in lymph flow within three days. This period of short-term adaptation corresponds closely to the critical period in the management of trauma patients. The responsible molecular pathways and the functional consequences of these adaptive changes are currently unknown. The central hypothesis for the proposed research is that mesenteric lymphatic vessels will adapt to mesenteric venous hypertension and intestinal edema by becoming better conduits and will adapt to downstream lymphatic obstruction by becoming better pumps. We will test this hypothesis by pursuing two specific aims. 1. Quantify changes in contractile function, biomechanics, calcium sensitivity and gene and protein expression in mesenteric lymphatic vessels in response to increased lymph flow induced by mesenteric venous hypertension. 2. Quantify changes in contractile function and gene and protein expression in mesenteric lymphatic vessels in response to decreased lymph flow induced by partial downstream lymphatic obstruction. We will use 2 bovine models, mesenteric venous hypertension and mesenteric lymphatic obstruction, to explore lymphatic adaptation. This research effort is expected to identify the molecular pathways and key changes in molecular expression by which lymphatic muscle adapts to altered hydrodynamic conditions associated with organ edema formation. In addition, it will quantify the functional and biomechanical consequences of that adaptation. This information will give direction to the development of new pharmacologic or molecular therapeutic measures designed to enhance lymphatic removal of edema fluid and reduce the time and expense required by that therapy.