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.
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.
| Rieder, Sadiye Amcaoglu; Nagarkatti, Prakash; Nagarkatti, Mitzi (2012) Multiple anti-inflammatory pathways triggered by resveratrol lead to amelioration of staphylococcal enterotoxin B-induced lung injury. Br J Pharmacol 167:1244-58 |
