Bidirectional Regulatory Interactions Between Lymph Vessel and Adjacent Tissues

描述（由申请人提供）：淋巴流动是液体和大分子稳态以及脂质和免疫细胞运输所必需的。历史上，运输淋巴管被认为是组织引流管，充其量只能推动淋巴。然而，由于肠系膜淋巴管（mlv）位于肠腔的生物侵袭环境和腹部内腔之间的边界，这些淋巴管从未被认为是肠系膜抗炎防御系统的有效成分，也从未被深入研究过。通过内皮衍生的一氧化氮和组胺的释放改变其收缩性，mlv可能影响炎症和/或污染淋巴成分下游扩散的速度，这取决于病原体的性质和炎症反应的程度/阶段。同时，mlv可能影响其附近发育良好的肥大细胞群。肥大细胞可能通过释放几种生物活性物质的组合来刺激或抑制邻近mlv的收缩性，进一步调整mlv的功能，以应对肠道和肠系膜炎症和水肿期间淋巴内条件的改变。该项目的中心假设是，肠系膜淋巴管和位于它们附近的肥大细胞作为一个双向生物系统发挥作用，其中两个组成部分相互影响，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，提议的研究将集中在以下具体目标上。目的1。确定受控的淋巴内应用代表炎症/污染淋巴成分的物质（炎症介质、微生物结构成分、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。确定肠系膜淋巴壁源性分子在炎症/污染淋巴出现后淋巴附近肥大细胞活化中的相对作用。目标3。阐明肥大细胞衍生分子在炎症/污染淋巴诱导肥大细胞活化后对肠系膜淋巴管收缩性的调节作用。拟议研究的创新方法将包括在控制淋巴内压力和流量下对淋巴管和邻近组织中细胞成分的功能状态进行综合评估，免疫组织化学和重要染料成像，药物阻断和遗传修饰。本研究不仅将对炎症和组织水肿发展过程中mlv -组织相互作用的机制提供新的多层次理解，而且将为更精确地识别“淋巴管-组织”系统中病理紊乱成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.