Effect of Resveratrol on Staphylococcal Enterotoxin B induced Vascular Leak

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，其特征是炎症细胞浸润到肺部并导致肺内皮（EndoC）和上皮（EpiC）细胞损伤。迄今为止，该病的发病机制尚不清楚，治疗选择也非常有限。在某些情况下，ALI进一步发展为急性肺窘迫综合征（ARDS），由于这会导致肺水肿和功能障碍，该综合征通常是致命的。本研究将采用葡萄球菌肠毒素B （SEB）致血管渗漏和ALI小鼠模型，探讨其发病机制，以及白藜芦醇（RES）的有效性。白藜芦醇是一种从红葡萄皮和其他植物中提取的化合物，通常被用作抗炎症的补充和替代药物（CAM）。该建议的中心假设是，RES对血管泄漏和ALI有效，后者主要是通过诱导细胞凋亡和抑制细胞因子的产生，由T和NK T细胞大量释放细胞因子引起的。本研究的具体目的是：(1)明确SEB诱导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细胞、NK T细胞和树突状细胞（DC）凋亡中的作用；(3)检测芳烃受体（AhR）和雌激素受体（ER）在Fas-FasL上调中的作用，从而在RES介导的SEB活化的T细胞和NK T细胞凋亡中的作用。为了解决具体的目标，将进行体外和体内研究。虽然本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治疗炎症性疾病。

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.