Effect of Resveratrol on Staphylococcal Enterotoxin B induced Vascular Leak

白藜芦醇对葡萄球菌肠毒素B所致血管渗漏的影响

• 批准号: 7678105
• 负责人: Sadiye Amcaoglu Rieder
• 金额: $ 3.56万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678105
• 关键词: Acute; Acute Lung Injury; Address; Alternative Medicine; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Apoptosis; Aryl Hydrocarbon Receptor; Biological Products; Bioterrorism; Blood Vessels; CD8B1 gene; Cardiovascular Diseases; Cells; Clinical; Complementary and alternative medicine; Cytokine Suppression; Cytolysis; Cytotoxic T-Lymphocytes; Dendritic Cells; Disease; Disease model; Distress; Effectiveness; Epithelial; Estrogen Receptors; Fellowship; Functional disorder; Goals; Grapes; Histocompatibility; Immune Cell Suppression; Immune system; In Vitro; Induction of Apoptosis; Infection; Infiltration; Inflammation; Inflammatory; Injury; Lead; Lung; Malignant Neoplasms; Mediating; Methods; Modality; Morus; Mus; Pancreatitis; Pathogenesis; Plants; Play; Pneumonia; Population; Process; Production; Property; Protein Binding; Proteins; Pulmonary Edema; Research; Research Personnel; Respiratory Failure; Resveratrol; Role; Sepsis; Skin; Staphylococcal Enterotoxin B; Superantigens; Syndrome; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Trauma; Up-Regulation; career; cytokine; experience; in vivo; insight; killer T cell; mortality; mouse model; novel; polyphenol; public health relevance; receptor; response; trans-resveratrol

DESCRIPTION (provided by applicant): Clinical disorders such as sepsis, trauma, pancreatitis and pneumonia can lead to acute lung injury (ALI) and respiratory failure, and this is characterized by infiltration of inflammatory cells into the lungs and results in damage to pulmonary endothelial (EndoC) and epithelial (EpiC) cells. The mechanism of disease remains unclear to date, and treatment options are very limited. In some cases, ALI further develops into acute lung distress syndrome (ARDS), and because this leads to pulmonary edema and dysfunction, this syndrome is often lethal. In the current study, a mouse model of vascular leak and ALI induced by Staphylococcal enterotoxin B (SEB) will be used to investigate the mechanism of pathogenesis, and the effectiveness of resveratrol (RES), a compound derived from red grape skin and other plants, commonly used as a complementary and alternative medicine (CAM) against inflammation. The central hypothesis of this proposal is that RES is effective against vascular leak and ALI which is caused by massive cytokine release by T and NK T cells, primarily through induction of apoptosis and suppression of cytokine production. The specific aims of this study are:(1) identify the exact mechanism of vascular leak induced by SEB and the role of RES as a treatment method, (2) investigate the role of Fas-FasL interactions in RES- induced apoptosis of T, NK T and dendritic (DC) cells, and (3) test the roles of Aryl hydrocarbon receptor (AhR) and Estrogen receptor (ER) in the upregulation of Fas-FasL, and consequently in the RES-mediated apoptosis of SEB-activated T and NK T cells. In order to address the specific aims, both in vitro and in vivo studies will be carried out. While the short term goal of this study is to identify the mechanisms through which RES suppresses the immune system, the long term objective is to develop better CAM therapies to treat inflammatory diseases. PUBLIC HEALTH RELEVANCE: This fellowship will not only enable the trainee to obtain necessary experience in CAM research but also help develop her career as an independent investigator. Moreover, SEB is a select agent and has potential in bioterrorism. Thus, understanding the mechanism of action of biological agents such as SEB and use of novel CAM treatment modalities such as RES, would provide great insights into clinical manifestations, and would assist in the management of mortality caused by such agents.

描述（由申请人提供）：临床疾病如败血症、创伤、胰腺炎和肺炎可导致急性肺损伤（ALI）和呼吸衰竭，其特征在于炎性细胞浸润到肺中并导致肺内皮（EndoC）和上皮（EpiC）细胞损伤。迄今为止，疾病的机制仍不清楚，治疗选择非常有限。在某些情况下，ALI进一步发展为急性肺窘迫综合征（ARDS），并且由于这导致肺水肿和功能障碍，该综合征通常是致命的。本研究采用金黄色葡萄球菌肠毒素B（SE B）诱导的小鼠血管渗漏和急性肺损伤模型，探讨其发病机制，以及白藜芦醇（RES）的有效性。该提议的中心假设是RES有效对抗血管渗漏和ALI，所述ALI由T和NK T细胞的大量细胞因子释放引起，主要通过诱导细胞凋亡和抑制细胞因子产生。本研究的具体目的是：（1）确定SEB诱导的血管渗漏的确切机制和RES作为治疗方法的作用，（2）研究Fas-FasL相互作用在RES诱导的T、NK T和树突状（DC）细胞凋亡中的作用，以及（3）测试芳烃受体（AhR）和雌激素受体（ER）在Fas-FasL上调中的作用，并因此在RES介导的SEB激活的T和NK T细胞凋亡中的作用。为了实现具体目标，将进行体外和体内研究。虽然这项研究的短期目标是确定RES抑制免疫系统的机制，但长期目标是开发更好的CAM疗法来治疗炎症性疾病。 公共卫生关系：该奖学金不仅使受训者能够获得CAM研究方面的必要经验，而且还有助于发展她作为独立调查员的职业生涯。此外，SEB是一种选择剂，具有生物恐怖主义的潜力。因此，了解SEB等生物制剂的作用机制和RES等新型CAM治疗方式的使用，将为临床表现提供更好的见解，并有助于管理此类制剂引起的死亡率。