Complement C1q and sepsis associated fatalities

1 补体C1q与败血症相关死亡 脓毒症是一种危及生命的全身性炎症状态，宿主对 一种感染。尽管导致疾病的关键的基于炎症的器官功能障碍 病理已发现，证候往往难以辨认，且目前 已公布的预后标准很难识别那些注定要死于这种疾病的人。续 我们在改善脓毒症疾病预后方面的努力失败，主要是由于 患者反应的异质性。即使年龄、性别和医学合并症相似， 尽管做出了很好的支持努力，但患者死亡率仍有很大的异质性。 在这里，(1)我们发现危重病人体内出现CD49c+中性粒细胞亚群 独立预测败血症的死亡率。(2)进一步发现中性粒细胞 与脓毒症死亡相关的亚群显著上调了 补体成分C1q。(3)重要的是，败血症幸存者的中性粒细胞表达较高。 C1q蛋白水平，而已故患者未能维持C1q蛋白的表达 中性粒细胞。(4)在小鼠脓毒症模型中，用中和抗体或有条件地封闭C1q 剔除中性粒细胞中的C1q导致败血症死亡率显著增加。(5)治疗 感染C1q的脓毒症小鼠显著提高了存活率。根据这些初步观察， 我们的主要假设是中性粒细胞C1q是一个可靠的败血症预后生物标志物。 死亡率。进一步的假设是，凋亡的中性粒细胞释放C1q来控制其 脓毒症期间严重损伤器官的自身清除。因此，C1q是一个可下药的靶点 用于减轻脓毒症患者的炎症损害，从而改善 生死存亡。在目标1中，我们将确定外周血中C1q表达之间的相关性 ICU患者中性粒细胞与脓毒症死亡率。目标2将调查通过哪些机制 C1q调节脓毒症的消退，包括C1q依赖的细胞凋亡吞噬作用 中性粒细胞与巨噬细胞分化。目标3将调查潜在的机制 异源C1q表达。目的4将确定重组C1q及其突变体的作用 变种对脓毒症小鼠存活的影响。综上所述，这项提案涉及各种机制 关于失调的宿主反应如何威胁到患者的生存并提供了一个分子 靶抑制高炎症反应的破坏性武器，同时促进 疾病解决和组织恢复。

1 Complement C1q and sepsis associated fatalities Sepsis is a life-threatening systemic inflammatory condition with dysregulated host responses to an infection. Although key hyperinflammation-based organ dysfunctions that drive disease pathology have been discovered, the syndrome is often difficult to recognize, and current published prognostic criteria poorly identify those destined to die with the condition. Continued failure of our efforts in improving disease prognosis in sepsis is mainly due to substantial heterogeneity in the patient response. Even with similar age, sex, and medical comorbidities, there is a substantial heterogeneity in the patient mortality despite excellent supportive efforts. Here, (1) we discovered that a subpopulation of CD49c+ neutrophil arising in critically ill patients independently predicts mortality from sepsis. (2) We further found that the neutrophil subpopulation associated with septic fatality dramatically upregulated gene expression of the complement component C1q. (3) Importantly, neutrophils from septic survivors expressed higher levels of C1q protein, while deceased patients failed to maintain C1q expression in their neutrophils. (4) In mouse sepsis models, blocking C1q with neutralizing antibodies or conditionally knocking out C1q in neutrophils led to a significant increase in septic mortality. (5) Treatment of septic mice with C1q drastically increased the survival. Based on these preliminary observations, our overarching hypothesis is that neutrophil C1q is a reliable prognostic biomarker of septic mortality. It is hypothesized further that apoptotic neutrophils release C1q to control their own clearance in critically injured organs during sepsis. Thus, C1q is a druggable target for attenuation of inflammatory damage to septic patients with resulting improvement in survival. In Aim 1, we will determine the correlation between C1q expression in peripheral blood neutrophils and sepsis mortality in ICU patients. Aim 2 will investigate the mechanisms by which C1q regulates the resolution of sepsis, including C1q-dependent phagocytosis of apoptotic neutrophils and differentiation of macrophages. Aim 3 will investigate mechanisms underlying the heterogenous C1q expression. Aim 4 will determine the effects of recombinant C1q and its mutant variants on the survival of septic mice. Taken together, this proposal addresses mechanisms regarding how the dysregulated host response threatens patient survival and offers a molecular target for dampening the destructive arms of the hyperinflammatory response while promoting disease resolution and tissue recovery.