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）：败血症是美国重症监护病房中死亡的主要原因，每年多达21万人死于该疾病。在动物模型和败血症的人类尸检研究中，肠道上皮细胞凋亡均升高。我们先前已经证明，抗凋亡蛋白Bcl-2的肠道特异性过表达与败血症的鼠模型后的生存率提高有关。这些研究已经在6-16周大的小鼠中进行，这与以前健康的10-17岁患者相对应。该人群几乎永远不会败血症，如果患者患有这种疾病，则折磨的患者只有很小的死亡机会。相比之下，绝大多数临床败血症发生在老年患者或患有严重的合并症的患者中。众所周知，老化的化粪池对治疗的反应明显与年轻的化粪池动物明显不同，这表明年轻的，健康的动物可能不是重症监护病房中的化粪池患者的适当替代物。在此应用中，将确定在衰老的动物或癌症患者中预防败血症诱导的肠道上皮凋亡的作用。将确定由Bcl-2的肠道过表达赋予的生存优势背后的机制，并将在年轻，健康的动物，老年动物和具有肿瘤的动物之间进行比较和对比。由于败血症是一种全身性疾病，机械研究将研究如何预防肠道上皮凋亡影响免疫系统。这些实验将是因为凋亡细胞是免疫抑制性的，并且预防细胞死亡应对免疫细胞分布和功能有次要影响。此外，肠道和免疫系统之间存在良好的“串扰”，这表明一种细胞类型的变化会改变另一种细胞类型。还将在肺炎中评估替代性抗凋亡疗法，以防止败血症诱导的细胞死亡，以确定这种方法是否降低了疾病中的死亡率，这是从局部肺部侮辱开始的，但由于继发性全身影响，杀死患者。