The impact of cancer on the pathophysiology of sepsis

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93000例。重要的是，癌症也是脓毒症患者死亡风险最高的合并症。我们已经创建了一个小鼠模型，复制了与先前健康的败血症患者相比，败血症癌症患者死亡率增加的情况。本提案的第一个目标是了解当宿主发生败血症时，先前存在的癌症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与此有关，因此将对每一个都进行详细检查。实验将在多个肿瘤系的脓毒症模型中进行，以确定结果是否适用于脓毒症或癌症类型。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凋亡可提高先前健康的败血症啮齿动物的存活率。然而，当这种策略用于患有癌症的脓毒症小鼠时，发现完全相反的情况，细胞凋亡预防要么显着增加死亡率（淋巴细胞），要么失去其功效（肠）。该提案试图理解为什么一种被广泛接受的有益的治疗方法，作为一种可能的治疗方法，如果在癌症背景下发生败血症，就会变得致命。由于目前正在努力将细胞凋亡预防转化为可用于脓毒症患者床边的治疗方法，因此该建议可能会改变进入标准和/或防止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，该建议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，这可能对这种既常见又高致命性的疾病具有重要意义。

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.