Complement C1q and sepsis associated fatalities

补充 C1q 和脓毒症相关死亡

• 批准号: 10832821
• 负责人: Minsoo Kim
• 金额: $ 7.95万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10832821
• 关键词: Acute; Address; Adult; Age; Apoptotic; Child; Chronic; Complement; Complement 1q; Complement component C1; Critical Care; Critical Illness; Disease; Failure; Functional disorder; Gene Expression; Heterogeneity; Immune response; Infection; Inflammatory; Inflammatory Response; Life; Macrophage; Medical; Modeling; Molecular Target; Morbidity - disease rate; Mus; Organ; Pathology; Patients; Phagocytosis; Prognostic Marker; Proteins; Publishing; Recombinants; Recovery; Resolution; Sepsis; Survivors; Syndrome; Tissues; Variant; arm; attenuation; comorbidity; conditional knockout; disease prognosis; druggable target; improved; mortality; mutant; neutralizing antibody; neutrophil; organ injury; patient response; peripheral blood; prognostic; septic; septic patients; severe injury; sex

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.

1 补充 C1q 和脓毒症相关死亡 脓毒症是一种危及生命的全身炎症性疾病，宿主反应失调 感染。尽管导致疾病的关键的基于过度炎症的器官功能障碍 病理学已被发现，该综合征往往难以识别，目前 已发表的预后标准很难识别那些注定会死于这种疾病的人。持续 我们在改善脓毒症疾病预后方面的努力失败主要是由于大量的 患者反应的异质性。即使年龄、性别和合并症相似， 尽管提供了出色的支持，但患者死亡率存在很大的异质性。 在这里，(1)我们发现危重患者中出现了 CD49c+ 中性粒细胞亚群 独立预测脓毒症死亡率。 (2)我们进一步发现中性粒细胞 与脓毒症死亡相关的亚群显着上调了 补体成分 C1q。 (3) 重要的是，脓毒症幸存者的中性粒细胞表达更高 C1q 蛋白水平，而已故患者未能在其体内维持 C1q 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阻断C1q 敲除中性粒细胞中的 C1q 会导致脓毒症死亡率显着增加。 (5) 治疗 感染 C1q 的脓毒症小鼠的存活率显着提高。根据这些初步观察， 我们的首要假设是中性粒细胞 C1q 是脓毒症可靠的预后生物标志物 死亡。进一步假设凋亡的中性粒细胞释放 C1q 来控制其 脓毒症期间严重受损器官的自身清除。因此，C1q 是一个可药物靶点 减轻脓毒症患者的炎症损伤，从而改善 生存。在目标 1 中，我们将确定外周血中 C1q 表达之间的相关性 ICU 患者的中性粒细胞和脓毒症死亡率。目标 2 将研究其机制 C1q 调节脓毒症的消退，包括 C1q 依赖性细胞凋亡吞噬作用 中性粒细胞和巨噬细胞的分化。目标 3 将研究潜在的机制 异质 C1q 表达。目标 4 将确定重组 C1q 及其突变体的效果 变异对脓毒症小鼠存活的影响。总而言之，该提案涉及机制 关于失调的宿主反应如何威胁患者的生存并提供分子 抑制过度炎症反应的破坏性武器，同时促进 疾病解决和组织恢复。

项目成果

Plasma Nitric Oxide Consumption Is Elevated and Associated With Adverse Outcomes in Critically Ill Patients.

血浆一氧化氮消耗量升高并与危重患者的不良后果相关。

• 发表时间: 2023-12-01
• 影响因子: 8.8
• 作者: Dony, Christina A;Illipparambil, Lijo C;Maeda, Tetsuro;Mroczek, Susan K;Rovitelli, Amy;Wexler, Orren;Malnoske, Michelle;Bice, Tristan;Fe, Alex Z;Storms, Casey R;Zhang, Jimmy;Schultz, Rebecca D;Pietropaoli, Anthony P
• 通讯作者: Pietropaoli, Anthony P