The Organ Specific Role of Superoxide Dismutase in Sepsis

描述（由申请人提供）： 严重脓毒症导致显著的发病率和死亡率。治疗选择有限，可能不成功。如果要找到更有效的治疗方法，关于这种疾病过程的机制信息是必不可少的。多种细胞类型的凋亡导致严重脓毒症的高发病率。在脓毒症中，细菌清除主要通过枯否细胞（肝脏的常驻巨噬细胞）实现。库普弗细胞在严重脓毒症期间经历凋亡，并且这与器官功能障碍和死亡率相关。其他器官也会影响菌血症的程度。胃肠道（GI）上皮细胞在脓毒症期间经历凋亡，从而允许肠道细菌移位穿过GI上皮并进入体循环。严重脓毒症时心肌细胞凋亡可能导致血流受损，并使其他器官功能障碍持续存在。最后，血管内皮细胞的凋亡有助于脓毒症中的微血管功能障碍，这可能导致组织灌注受损。已知线粒体抗氧化剂响应于氧化应激（例如与脓毒症相关的氧化应激）而防止细胞凋亡。超氧化物歧化酶2（SOD 2）是最丰富的线粒体抗氧化剂。已经出现了两种可能直接影响线粒体抗氧化功能的途径。这些途径涉及通过胰岛素样生长因子1（IGF-1）和血管紧张素II（AngII）的信号传导。值得注意的是，IGF-1水平在严重脓毒症中降低，而AngII上调。AngII是一种有效的血管收缩剂，是氧化应激和细胞凋亡的重要决定因素。缺乏循环IGF-1会损害细胞存活和功能。该建议的假设是血管紧张素II和IGF-1之间的病理相互作用影响特定器官中的SOD 2水平，并导致肝脏细菌清除受损和严重脓毒症的不良结局。在目标1中，我们将使用我们定义的急性脓毒症模型来研究SOD 2的器官特异性作用。我们将产生组织特异性SOD 2敲除小鼠，以确定受损的SOD 2如何有助于脓毒症中的细菌清除和存活。在目标2中，我们将使用相同的模型（和目标1中产生的小鼠）来研究IGF-1和血管紧张素II在脓毒症期间器官特异性SOD 2活性中的作用。 公共卫生相关性：本提案中概述的研究对脓毒症研究领域至关重要，并且很有可能转化为涉及人类受试者的研究。这些实验将首次破译每个器官系统对细菌清除和脓毒症结果的影响。这些研究有可能极大地影响这种复杂疾病的管理，这种疾病死亡率高，而且到目前为止，改善结果的治疗选择很少。

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.