The impact of cancer on the pathophysiology of sepsis

描述（由申请人提供）：癌症是脓毒症患者中最常见的合并症，每年有近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。我们已经建立了一个小鼠模型，该模型复制了与先前健康的脓毒症患者相比，脓毒症癌症患者的死亡率增加。该提案的第一个目标是了解当宿主发生败血症时，预先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参与其中，因此将详细检查其中的每一个。将在具有多种肿瘤系的多种脓毒症模型中进行实验，以确定结果是否具有普遍性或对脓毒症类型或癌症类型具有特异性。此外，来自多个研究小组的大量数据表明，淋巴细胞或肠上皮细胞中的细胞凋亡预防可改善先前健康的脓毒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，发现与凋亡预防完全相反的是显著增加死亡率（淋巴细胞）或失去其功效（肠）。该提案旨在了解为什么一种被广泛接受为患者可能治疗方法的有益疗法在癌症背景下发生败血症时会变得致命。由于目前正在努力将细胞凋亡预防转化为可以在床边用于脓毒症患者的治疗，因此该提案可能会改变入选标准和/或防止接受脓毒症细胞凋亡预防临床试验的患者意外死亡。因此，该提案旨在了解脓毒症中可能需要与“典型”脓毒症宿主不同的治疗方法的亚群，这可能对非常常见且高度致命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.