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）：癌症是化粪池中最常见的合并症，每年近93,000例病例。重要的是，癌症也是败血症患者死亡风险最高的合并症。我们创建了一个鼠模型，与以前健康的败血症患者相比，癌症患者的死亡率增加。该提案的第一个目标是了解可能的机制，当宿主发育败血症时，预先存在的癌症会增加死亡率。基于初步数据，免疫系统和肠道完整性似乎都涉及，因此将详细检查其中的每一个。实验将在具有多个肿瘤系的多种败血症模型中进行，以确定结果是败血症类型还是癌症类型。此外，还有来自多个研究组的大量数据，这些数据可以预防淋巴细胞或肠上皮的细胞凋亡，可改善败血症以前健康啮齿动物的生存。但是，当这种策略用于患有癌症的化粪池小鼠时，预防凋亡的确切相反可以显着增加死亡率（淋巴细胞）或失去其疗效（肠）。该提案试图理解为什么如果在癌症的情况下发生败血症的情况下，将广泛接受为患者的治疗方法的有益疗法会变致命。由于目前正在努力将预防细胞凋亡转化为可以在床旁用于化粪池患者的治疗，因此该提案可能会改变入学标准和/或预防预防细胞凋亡的临床试验的患者中无意中的死亡率。因此，该提案试图了解败血症内的亚群，该亚群可能需要与“典型”化粪池宿主不同的治疗方法，这可能对既普遍又高度致命的疾病具有重要意义。