Bidirectional Regulatory Interactions Between Lymph Vessel and Adjacent Tissues

描述（由申请方提供）：淋巴流对于液体和大分子稳态以及脂质和免疫细胞的运输是必需的。在历史上，运输淋巴管被认为是组织引流管，最多能够推动淋巴。然而，肠系膜淋巴管（MLV）位于肠腔的生物侵袭性环境和腹部的内部隔室之间的边界，这些淋巴管从未被考虑和深入研究为肠系膜的抗炎防御系统的活性组分。通过内皮源性释放一氧化氮和组胺改变其收缩性，MLV可影响炎症和/或污染淋巴液组分的下游扩散速度，这取决于病原体的性质和炎症反应的程度/阶段。与此同时，MLV可能会影响位于其附近的发育良好的肥大细胞群。肥大细胞可以通过释放几种生物活性物质的组合来刺激或抑制相邻MLV的收缩性，进一步适应MLV的功能，以响应肠道和肠系膜炎症和水肿期间改变的淋巴内条件。拟议项目的中心假设是，肠系膜淋巴管和位于其附近的肥大细胞作为一个双向生物系统发挥作用，其中两种成分相互影响，并根据淋巴内容物中炎症相关变化的性质调整其功能活性水平。为了检验中心假设，拟议的研究将集中在以下具体目标。目标1.确定受控淋巴内应用代表炎症/污染淋巴成分的物质（炎症介质、微生物结构组分、抗原）对肠系膜淋巴管收缩性和附近肥大细胞活化的影响。目标2.确定肠系膜淋巴管壁衍生分子对炎症/污染淋巴出现后位于淋巴管附近的肥大细胞活化的相对作用。目标3。阐明肥大细胞衍生分子在炎症/污染淋巴液诱导肥大细胞活化后调节肠系膜淋巴管收缩性中的作用。拟议研究的创新方法将包括在控制淋巴管内压力和流量、免疫组织化学和活体染料成像、药理学阻断和遗传修饰下对邻近组织中淋巴管和细胞成分的功能状态进行综合评价。拟议的研究不仅将提供对炎症和组织水肿发展过程中MLV-组织相互作用机制的新的多层次理解，而且将为更精确地识别“淋巴管-组织”系统病理干扰组分的治疗靶点提供独特的基础。

DESCRIPTION (provided by applicant): Lymph flow is necessary for fluid and macromolecular homeostasis as well as transportation of lipids and immune cells. Historically, the transporting lymphatic vessels were considered as tissue-draining tubes, which at best were able to propel lymph. However, mesenteric lymphatic vessels (MLVs) being located at the border between the biologically aggressive environment of the gut lumen and inner compartments of the abdomen, these lymph vessels have never been considered and studied in depth as an active component of the anti- inflammatory defense system of the mesentery. By changing their contractility through endothelium-derived release of nitric oxide and histamine, MLVs may influence the rapidity of downstream spread of the components of inflamed and/or contaminated lymph, depending on the nature of the pathogen and the degree/stage of the inflammatory response. At the same time, MLVs may influence a well-developed population of mast cells located nearby them. Mast cells may stimulate or inhibit the contractility of adjacent MLVs through the release of a combination of several biologically active substances, further adapting the function of MLVs in response to altered intralymphatic conditions during gut and mesenteric inflammation and edema. The central hypothesis of the proposed project is that mesenteric lymphatic vessels and mast cells located in close proximity to them are functioning as a bi-directional biological system, in which both components are influencing each other and adapting the levels of their functional activity depending on the nature of the inflammation-related changes in lymph content. To test the central hypothesis the proposed studies will focus on following specific aims. Aim 1. To determine the effects of controlled intralymphatic application of substances representing elements of inflamed/contaminated lymph (inflammatory mediators, components of microbial structures, antigen) on contractility of mesenteric lymphatic vessels and on activation of mast cells located near them. Aim 2. To determine the relative roles of mesenteric lymphatic wall-derived molecules on activation of mast cells located near lymphatics subsequent to appearance of the inflamed/contaminated lymph. Aim 3. To elucidate the roles of mast cell-derived molecules in regulation of the contractility of mesenteric lymphatic vessels after mast cell activation induced by inflamed/contaminated lymph. The innovative approach of the proposed research will include combined evaluations of the functional status of lymphatic vessels and cellular elements in adjacent tissues under controlled intralymphatic pressure and flow, immunohistochemical and vital dye imaging, pharmacological blockade and genetic modifications. The proposed research will not only provide novel multi-level understanding of the mechanisms involved in MLV-tissue interactions during the development of inflammation and tissue edema, but will offer a unique basis for more precise identification of therapeutic targets of the pathologically disturbed components of the "lymphatic vessel-tissue" system.