The impact of cancer on the pathophysiology of sepsis

癌症对脓毒症病理生理学的影响

• 批准号: 8822311
• 负责人: Craig M Coopersmith
• 金额: $ 29.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822311
• 关键词: Adenocarcinoma Cell; Animal Model; Animals; Apoptosis; Autopsy; BCL2 gene; Cancer Patient; Cessation of life; Clinical; Clinical Trials; Comorbidity; Data; Development; Disease; Etiology; Functional disorder; General Population; Goals; Health; Health Care Costs; Human; Immune response; Immune system; Immunosuppression; Incidence; Infection; Injection of therapeutic agent; Intestines; Ligation; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediator of activation protein; Modeling; Mus; Organ; Palpable; Pancreatic Adenocarcinoma; Patients; Play; Pneumonia; Prevention; Pseudomonas aeruginosa; Puncture procedure; Research Personnel; Rodent; Role; Secondary to; Sepsis; Solid Neoplasm; Spleen; Study models; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Translating; Wild Type Mouse; apoptosis in lymphocytes; base; cancer therapy; cancer type; gastrointestinal epithelium; high risk; improved; interest; mortality; overexpression; prevent; research study; response; septic; tumor

DESCRIPTION (provided by applicant): Cancer is the most common comorbidity in septic patients with nearly 93,000 cases annually. Importantly, cancer is also the comorbidity associated with the highest risk of death in patients with sepsis. We have created a murine model that replicates the increased mortality seen in septic patients with cancer compared to previously healthy patients who develop sepsis. The first goal of this proposal is to understand possible mechanisms through which pre-existing cancer increases mortality when a host develops sepsis. Based upon preliminary data, both the immune system and gut integrity appear to be involved, so each of these will be examined in detail. Experiments will be performed in multiple models of sepsis with multiple tumor lines to determine whether results are generalizable or specific to either type of sepsis or type of cancer. Additionally, there is extensive data from multiple investigative groups that apoptosis prevention in either lymphocytes or the gut epithelium improves survival in previously health rodents with sepsis. However, when this strategy is used in septic mice with cancer, the precise opposite is found with apoptosis prevention either markedly increasing mortality (lymphocytes) or losing its efficacy (intestine). The proposal seeks to understand why a beneficial therapy that has widespread acceptance as a possible treatment approach for patients turns deadly if sepsis occurs in the setting of cancer. Since efforts are currently being made to translate apoptosis prevention into treatment that can be used at the bedside for septic patients, this proposal could potentially change entry criteria and/or prevent inadvertent mortality in patients undergoing clinical trials of apoptosis prevention in sepsis. Thus, the proposal seeks to understand a subpopulation within sepsis that may require a different therapeutic approach than a "typical" septic host, and this may have significant implications in a disease that is both very common and highly lethal.

描述（由申请人提供）：癌症是脓毒症患者最常见的合并症，每年有近 93,000 例病例。重要的是，癌症也是脓毒症患者死亡风险最高的合并症。我们创建了一个小鼠模型，该模型复制了与先前健康的脓毒症患者相比，患有癌症的脓毒症患者死亡率增加的情况。该提案的第一个目标是了解当宿主患败血症时，已有的癌症会增加死亡率的可能机制。根据初步数据，免疫系统和肠道完整性似乎都参与其中，因此将详细检查其中每一个。将在具有多种肿瘤系的多种脓毒症模型中进行实验，以确定结果对于脓毒症类型或癌症类型是否具有普遍性或特异性。此外，来自多个研究小组的大量数据表明，预防淋巴细胞或肠道上皮细胞的凋亡可以提高患有脓毒症的健康啮齿动物的存活率。然而，当这种策略用于患有癌症的脓毒症小鼠时，发现细胞凋亡预防恰恰相反，要么显着增加死亡率（淋巴细胞），要么失去功效（肠道）。该提案旨在了解为什么一种被广泛接受的有益疗法，作为患者可能的治疗方法，如果在癌症环境中发生脓毒症，却会变得致命。由于目前正在努力将细胞凋亡预防转化为可在脓毒症患者床边使用的治疗方法，因此该提案可能会改变接受脓毒症细胞凋亡预防临床试验的患者的进入标准和/或防止意外死亡。因此，该提案旨在了解脓毒症中的一个亚群，该亚群可能需要与“典型”脓毒症宿主不同的治疗方法，这可能对一种非常常见且高度致命的疾病产生重大影响。