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.
A major problem contributing to sickness and death in trauma patients following emergency resuscitation is intestinal dysfunction caused by accumulation of tissue fluid within the wall of the intestine. The lymphatic system plays a crucial role in limiting the accumulation of this fluid by returning tissue fluid to the blood stream. This research effort is expected to identify how lymphatic vessels adapt to these conditions and, thus, provide information for development of new therapies to promote fluid removal from the intestine.
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