Gut Epithelial Apopotosis in Shock and Sepsis

休克和脓毒症中的肠道上皮细胞凋亡

• 批准号: 7921712
• 负责人: Craig M Coopersmith
• 金额: $ 1.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2009-11-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921712
• 关键词: 17 year old; Age; Aging; Animal Model; Animals; Apoptosis; Apoptotic; Autopsy; Cause of Death; Cell Death; Cells; Chronic; Clinical; Critical Illness; Disease; Epithelial; Epithelial Cells; Gene Deletion; Human; Immune; Immune system; Immunosuppression; Immunosuppressive Agents; Inflammation; Intensive Care Units; Intestines; Lead; Lung; Malignant Neoplasms; Methods; Modeling; Morbidity - disease rate; Motor; Mus; Neoplasms; Organism; Patients; Play; Pneumonia; Population; Prevention; Proteins; Radiation; Role; Secondary to; Sepsis; Sepsis Syndrome; Shock; Systemic disease; Toxic effect; Treatment Efficacy; United States; acute stress; aged; cancer diagnosis; cell type; clinically relevant; improved; in vivo; intestinal epithelium; killings; mortality; novel strategies; older patient; overexpression; patient population; prevent; research study; septic; tetrahydrobiopterin; uptake

DESCRIPTION (provided by applicant): Sepsis is the leading cause of death in intensive care units in the United States, with up to 210,000 people dying from the disease annually. Gut epithelial apoptosis is elevated in both animal models and human autopsy studies of sepsis. We have previously demonstrated that gut-specific overexpression of the anti- apoptotic protein Bcl-2 is associated with improved survival following murine models of sepsis. These studies have been performed in 6-16 week old mice, which correspond to previously healthy 10-17 year old patients. This population almost never gets septic, and afflicted patients have only a small chance of dying if they do develop the disease. In contrast, the vast majority of clinical sepsis occurs in aged patients or those with severe pre-existing co-morbidities. It is known that aged septic animals respond markedly different to therapy than young septic animals, suggesting that young, previously healthy animals might not be appropriate surrogates for septic patients in intensive care units. In this application, the effect of preventing sepsis- induced gut epithelial apoptosis in either aged animals or those with cancer will be determined. Mechanisms underlying the survival advantage conferred by gut overexpression of Bcl-2 will be determined and will be compared and contrasted between young, previously healthy animals, aged animals, and animals with neoplasia. Since sepsis is a systemic disease, mechanistic studies will examine how preventing gut epithelial apoptosis influences the immune system. These experiments will be performed because apoptotic cells are immunosuppressive and preventing cell death should have secondary effects on immune cell distribution and function. In addition, there is well- established "crosstalk" between the gut and the immune system suggesting changes in one cell type will alter the other. Alternative anti-apoptotic therapies to prevent sepsis- induced cell death will also be evaluated in pneumonia, to determine if this approach decreases mortality in a disease which starts with a local pulmonary insult but kills patients in large part due to secondary systemic effects.

描述（由申请人提供）：脓毒症是美国重症监护室的首要死因，每年有多达 21 万人死于该病。在脓毒症的动物模型和人体尸检研究中，肠上皮细胞凋亡均升高。我们之前已经证明，抗凋亡蛋白 Bcl-2 的肠道特异性过度表达与脓毒症小鼠模型存活率的提高有关。这些研究是在 6-16 周龄的小鼠中进行的，这些小鼠相当于之前健康的 10-17 岁患者。这个人群几乎从来不会患上败血症，而且患者如果患上这种疾病，死亡的可能性也很小。相比之下，绝大多数临床脓毒症发生在老年患者或患有严重合并症的患者中。众所周知，老年化脓性动物对治疗的反应与年轻化脓性动物明显不同，这表明年轻的、先前健康的动物可能不适合替代重症监护病房的化脓性患者。在本申请中，将确定在老年动物或患有癌症的动物中预防脓毒症诱导的肠上皮细胞凋亡的效果。将确定肠道 Bcl-2 过度表达所赋予的生存优势的机制，并将在年轻的、先前健康的动物、老年动物和患有肿瘤的动物之间进行比较和对比。由于脓毒症是一种全身性疾病，因此机制研究将探讨预防肠道上皮细胞凋亡如何影响免疫系统。进行这些实验是因为凋亡细胞具有免疫抑制作用，防止细胞死亡会对免疫细胞的分布和功能产生二次影响。此外，肠道和免疫系统之间存在明确的“串扰”，表明一种细胞类型的变化会改变另一种细胞类型。还将在肺炎中评估预防脓毒症诱导的细胞死亡的替代抗凋亡疗法，以确定这种方法是否可以降低这种疾病的死亡率，这种疾病始于局部肺部损伤，但由于继发性全身效应而导致大部分患者死亡。