Bidirectional Regulatory Interactions Between Lymph Vessel and Adjacent Tissues

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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.