The impact of cancer on the pathophysiology of sepsis

描述(申请人提供)：癌症是败血症患者最常见的共病，每年有近93,000例。重要的是，在脓毒症患者中，癌症也是死亡风险最高的共病。我们已经建立了一个小鼠模型，复制了癌症脓毒症患者与以前健康的脓毒症患者相比死亡率增加的情况。这项建议的第一个目标是了解先前存在的癌症在宿主发生脓毒症时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涉及到，因此将对每一项进行详细检查。实验将在具有多个肿瘤系的多种脓毒症模型中进行，以确定结果是否对任何类型的脓毒症或癌症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，无论是淋巴细胞还是肠道上皮细胞的凋亡预防，都可以提高患有脓毒症的健康啮齿动物的存活率。然而，当这一策略用于患有癌症的脓毒症小鼠时，发现恰恰相反的是，细胞凋亡的预防要么显著增加死亡率(淋巴细胞)，要么失去效力(肠道)。该提案试图了解，为什么一种被广泛接受为患者可能的治疗方法的有益疗法，如果在癌症背景下发生脓毒症，会变得致命。由于目前正在努力将预防细胞凋亡转化为可用于脓毒症患者床边的治疗，这项提议可能会改变进入标准和/或防止正在接受脓毒症细胞凋亡预防临床试验的患者的意外死亡。因此，该提案试图了解脓毒症中可能需要与“典型”败血症宿主不同的治疗方法的亚群，这可能对一种非常常见且高度致命的疾病具有重大影响。

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.