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The Organ Specific Role of Superoxide Dismutase in Sepsis

超氧化物歧化酶在脓毒症中的器官特异性作用

基本信息

批准号：
7699506
负责人：
ALIX ASHARE
金额：
$ 7.9万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7699506
关键词：
Acute Affect Alveolar Macrophages Angiotensin II Angiotensin Receptor Antioxidants Apoptosis Bacteremia Bacteria Bacterial Translocation Blood Circulation Blood flow Cardiac Myocytes Cell Survival Complex Data Disease Enterobacteriaceae Epithelial Cells Evolution Functional disorder Hepatic Individual Infection Inflammatory Response Insulin-Like Growth Factor I Knockout Mice Kupffer Cells Lead Liver Maintenance Methods Mitochondria Modeling Morbidity - disease rate Myocardial Myocardium Organ Outcome Oxidative Stress Pathologic Pathway interactions Perfusion Pharmacologic Substance Process Research Reticuloendothelial System Role Sepsis Signal Transduction Superoxide Dismutase Therapeutic Time Tissues Translating Up-Regulation Vascular Endothelial Cell Vasoconstrictor Agents base body system cell type depressed design gastrointestinal gastrointestinal epithelium human SOD2 protein human subject improved interest macrophage mortality mouse model oxidant stress prevent public health relevance research study response skeletal

项目摘要

DESCRIPTION (provided by applicant): Severe sepsis results in significant morbidity and mortality. Treatment options are limited and potentially unsuccessful. Mechanistic information on this disease process is essential if more efficacious treatments are to be found. Apoptosis of multiple cells types contributes to the high morbidity with severe sepsis. In sepsis, bacterial clearance is primarily achieved by Kupffer cells, the resident macrophages of the liver. Kupffer cells undergo apoptosis during severe sepsis, and this is associated with organ dysfunction and mortality. Other organs impact the degree of bacteremia as well. Gastrointestinal (GI) epithelial cells undergo apoptosis during sepsis allowing enteric bacteria to translocate across the GI epithelium and enter the systemic circulation. Cardiac myocyte apoptosis during severe sepsis could contribute to impaired blood flow and perpetuate dysfunction of other organs. Lastly, apoptosis of vascular endothelial cells contributes to microvascular dysfunction in sepsis, which may lead to impaired tissue perfusion. Mitochondrial antioxidants are known to prevent cellular apoptosis in response to oxidative stress such as that associated with sepsis. Superoxide dismutase 2 (SOD2) is the most abundant mitochondrial antioxidant. Two pathways have emerged which may directly influence mitochondrial antioxidant function. These pathways involve signaling via insulin-like growth factor 1 (IGF-1) and angiotensin II (AngII). It is of note that IGF-1 levels are decreased in severe sepsis, while AngII is upregulated. AngII is a potent vasoconstrictor that is an important determinant of oxidant stress and cellular apoptosis. Lack of circulating IGF-1 impairs cell survival and function. The hypothesis of this proposal is that pathologic interactions between angiotensin II and IGF-1 influence SOD2 levels in specific organs and contribute to impaired hepatic bacterial clearance and poor outcome in severe sepsis. In Aim 1, we will use our defined acute sepsis model to study the organ-specific role of SOD2. We will generate tissue-specific SOD2 knock-out mice to determine how impaired SOD2 contributes to bacterial clearance and survival in sepsis. In Aim 2, we will use the same model (and mice generated in Aim 1) to study the role of IGF-1 and angiotensin II in organ-specific SOD2 activity during sepsis. PUBLIC HEALTH RELEVANCE: The studies outlined in this proposal are essential to the field of sepsis research and have a high likelihood of translating into studies involving human subjects. These experiments will decipher, for the first time, each individual organ system's effect on bacterial clearance and outcome in sepsis. These studies have the potential to greatly impact the management of a complex disease which has a high mortality and, thus far, few therapeutic options which improve outcome.

描述（由申请人提供）：