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Role of mesenteric lymphatics and dietary endotoxin in metabolic syndrome

肠系膜淋巴管和膳食内毒素在代谢综合征中的作用

基本信息

批准号：
8847710
负责人：
MARIAPPAN MUTHUCHAMY
金额：
$ 29.2万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8847710
关键词：
ADD-1 protein Address Adipose tissue Affect Animal Model Animals Blood Body Fluids Calcium Cardiovascular Diseases Cells Central obesity Characteristics Chronic Chylomicrons Cues Cyclic GMP Data Development Diagnostic Diet Dietary Fats Disease Progression Dyslipidemias Endotoxins Enzyme-Linked Immunosorbent Assay Exhibits Fatty Liver Fatty acid glycerol esters Fructose Functional disorder Health Homeostasis Hypertension IL8 gene Immune Immune system Immunofluorescence Immunologic Immunohistochemistry In Situ Inflammation Inflammatory Interleukin-13 Interleukin-4 Interleukin-5 Interleukins Intestines Lead Length Lipids Lipopolysaccharides Liver diseases Lymph Lymphatic Lymphatic System Lymphatic vessel MAP Kinase Gene MAPK14 gene Measurement Measures Mediating Mesentery Metabolic Metabolic syndrome Metabolism MicroRNAs Modeling Molecular Muscle Cells Neuromodulator Non-Insulin-Dependent Diabetes Mellitus Pathologic Pathway interactions Peroxisome Proliferator-Activated Receptors Phosphorylation Physiological Play Preparation Production Publishing Rattus Recruitment Activity Regulation Risk Role Route Small Intestines Structure Substance P Testing Tissues Tumor Necrosis Factor-alpha absorption atherogenesis base cell type chemokine cytokine eosinophil fasting glucose genetic regulatory protein improved in vivo lipid metabolism lymph flow lymphatic pump macrophage neutrophil peptide hormone pressure public health relevance research study tool trafficking

项目摘要

DESCRIPTION (provided by applicant): Although more than 95% of dietary lipids are absorbed from the small intestine via the intestinal lymphatics, transported via the mesenteric collecting lymphatics through the lymphatic network en route to the blood, the role of lymph transport in the regulation of lipid metabolism is poorly understood. We have recently shown that high fructose diet-induced metabolic syndrome (MetSyn) rats exhibit impaired mesenteric lymphatic function. Dietary endotoxin readily associates with chylomicrons and are primarily absorbed through the mesenteric lymphatics along with many other gut peptides and hormones, suggesting that the primary trafficking of dietary endotoxins, such as, lipopolysaccharide (LPS) is via lymphatics. Hence, important questions remain unanswered: 1) what are the roles of lymphatic function in and responsiveness to dietary endotoxin and 2) how does that affect the progression of MetSyn. Our preliminary data show that immune cells, eosinophils and neutrophils are present on or adjacent to the lymphatic wall, and that the number of these immune cells on the lymphatic wall is decreased in LPS-induced inflamed mesenteric tissue. These data provide the basis for our central hypothesis: That dietary endotoxins alters the local cues (major cytokines of eosinophil and neutrophil: IL-4, IL-5, IL-8 and IL-13) in the mesenteric milieu that impairs lymphatic function and chylomicron transport, which leads to dyslipidemia and mesenteric adipose accumulation, both key pathologic determinants of the development of MetSyn. We will use the high-fructose and high-fat diet-induced MetSyn rat models and a LPS-induced inflammation model to determine the roles of the lymphatic system in the pathophysiology of MetSyn. Specific Aims are: 1) To demonstrate the linkages between dietary endotoxins, pro-inflammatory cytokines and lymphatic function during the development of MetSyn; 2) To determine the functional consequences and molecular mechanisms of reduced lymph transport in the development of MetSyn; and 3) To test the roles of micro RNAs (miRs) that interconnect the regulation of IL-8, IL-4, IL-5 and IL-13 in modulating lymphatic function during the development of MetSyn. We will use whole-mount mesenteric preparations for immunohistochemical studies, in situ preparations for lymph flow and lymphatic contractility, isolated/cannulated vessels for contractile characteristics of lymphatics, wire-myograph studies for length- tension and force-calcium measurements. These experiments will specifically address how dietary endotoxins effect the M1 and M2 macrophage polarization on lymphatics and the mechanisms by which the eosinophil and neutrophil interleukins, IL-4, IL-5, IL-8 and IL-13, and miR-19a, 93, 200c and 203 in lymphatic muscle cells regulate the lymphatic structure and function. Thus, this proposal will identify important targets bridging the mesentery milieu and lymphatic function, which could potentially provide diagnostic tools and/or therapies to improve lymph transport, and thus improve health in chronic inflammatory conditions such as MetSyn.

描述（由申请人提供）：虽然95%以上的膳食脂质是从小肠经肠淋巴吸收，经肠系膜集淋巴管经淋巴网络输送到血液，但淋巴运输在调节脂质代谢中的作用尚不清楚。我们最近的研究表明，高果糖饮食诱导的代谢综合征（MetSyn）大鼠表现出肠系膜淋巴功能受损。膳食内毒素很容易与乳糜微粒结合，并主要通过肠系膜淋巴管与许多其他肠道肽和激素一起吸收，这表明膳食内毒素（如脂多糖（LPS））的主要运输是通过淋巴管。因此，重要的问题仍未得到解答：1)淋巴功能在饮食内毒素反应中的作用和2)如何影响MetSyn的进展。我们的初步数据显示，免疫细胞、嗜酸性粒细胞和中性粒细胞存在于淋巴壁上或邻近淋巴壁，并且在lps诱导的炎症肠系膜组织中，淋巴壁上这些免疫细胞的数量减少。这些数据为我们的中心假设提供了基础：饮食内毒素改变了肠系膜环境中的局部线索（嗜酸性粒细胞和中性粒细胞的主要细胞因子：IL-4、IL-5、IL-8和IL-13），从而损害淋巴功能和乳糜微粒运输，导致血脂异常和肠系膜脂肪堆积，这两者都是MetSyn发展的关键病理决定因素。我们将使用高果糖和高脂肪饮食诱导的MetSyn大鼠模型和lps诱导的炎症模型来确定淋巴系统在MetSyn病理生理中的作用。具体目的是：1)揭示MetSyn发育过程中饮食内毒素、促炎细胞因子与淋巴功能之间的联系；2)确定MetSyn发育过程中淋巴运输减少的功能后果和分子机制；3)在MetSyn发育过程中，检测连接IL-8、IL-4、IL-5和IL-13调控的微rna （miRs）在调节淋巴功能中的作用。我们将使用全挂载肠系膜制剂进行免疫组织化学研究，原位制备淋巴流动和淋巴收缩性，分离/插管血管用于淋巴收缩特征，钢丝肌图研究用于长度-张力和力-钙测量。这些实验将专门研究膳食内毒素如何影响淋巴系统中M1和M2巨噬细胞的极化，以及淋巴肌肉细胞中嗜酸性粒细胞和中性粒细胞白介素、IL-4、IL-5、IL-8和IL-13以及miR-19a、93、200c和203调节淋巴结构和功能的机制。因此，该建议将确定连接肠系膜环境和淋巴功能的重要靶点，这可能为改善淋巴运输提供诊断工具和/或治疗方法，从而改善慢性炎症疾病（如MetSyn）的健康状况。