From the Division of Pulmonary Inflammation (H.M.-R., S.-M.W., B.G., J.L., K.H., K.R., E.L., M.W.) the Department of Infectious Diseases and Respiratory Medicine (H.M.-R., U.K., N.S., M.W.), Charité - University Medicine Berlin (Charité - Universitätsmedizin Berlin), corporate member of Free University of Berlin (Freie Universität Berlin), Humboldt University of Berlin (Humboldt-Universität zu Berlin), and Berlin Institute of Health, Berlin, Germany Institute of Anatomy and Cell Biology, Saarland University, Homburg/Saar, Germany (T.T.) Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany (M.S., P.A.) NOXXON Pharma AG, Berlin, Germany (C.M., K.H., S.K., A.V.) Institute of Veterinary Pathology, Free University of Berlin (Freie Universität Berlin), Berlin, Germany (T.C.F., J.H.) German Center for Lung Research, Giessen, Germany (associate members N.S., M.W.).
Anesthesiology. 2020 Apr;132(4):795-807. doi: 10.1097/ALN.0000000000003149.
Community-acquired pneumonia and associated sepsis cause high mortality despite antibiotic treatment. Uncontrolled inflammatory host responses contribute to the unfavorable outcome by driving lung and extrapulmonary organ failure. The complement fragment C5a holds significant proinflammatory functions and is associated with tissue damage in various inflammatory conditions. The authors hypothesized that C5a concentrations are increased in pneumonia and C5a neutralization promotes barrier stabilization in the lung and is protective in pneumococcal pulmonary sepsis.
The authors investigated regulation of C5a in pneumonia in a prospective patient cohort and in experimental pneumonia. Two complementary models of murine pneumococcal pneumonia were applied. Female mice were treated with NOX-D19, a C5a-neutralizing L-RNA-aptamer. Lung, liver, and kidney injury and the inflammatory response were assessed by measuring pulmonary permeability (primary outcome), pulmonary and blood leukocytes, cytokine concentrations in lung and blood, and bacterial load in lung, spleen, and blood, and performing histologic analyses of tissue damage, apoptosis, and fibrin deposition (n = 5 to 13).
In hospitalized patients with pneumonia (n = 395), higher serum C5a concentrations were observed compared to healthy subjects (n = 24; 6.3 nmol/l [3.9 to 10.0] vs. 4.5 nmol/l [3.8 to 6.6], median [25 to 75% interquartile range]; difference: 1.4 [95% CI, 0.1 to 2.9]; P = 0.029). Neutralization of C5a in mice resulted in lower pulmonary permeability in pneumococcal pneumonia (1.38 ± 0.89 vs. 3.29 ± 2.34, mean ± SD; difference: 1.90 [95% CI, 0.15 to 3.66]; P = 0.035; n = 10 or 11) or combined severe pneumonia and mechanical ventilation (2.56 ± 1.17 vs. 7.31 ± 5.22; difference: 4.76 [95% CI, 1.22 to 8.30]; P = 0.011; n = 9 or 10). Further, C5a neutralization led to lower blood granulocyte colony-stimulating factor concentrations and protected against sepsis-associated liver injury.
Systemic C5a is elevated in pneumonia patients. Neutralizing C5a protected against lung and liver injury in pneumococcal pneumonia in mice. Early neutralization of C5a might be a promising adjunctive treatment strategy to improve outcome in community-acquired pneumonia.
社区获得性肺炎和相关脓毒症尽管进行了抗生素治疗，但仍导致高死亡率。不受控制的炎症宿主反应通过驱动肺和肺外器官衰竭导致不利的结果。补体片段 C5a 具有显著的促炎功能，并与各种炎症状态下的组织损伤有关。作者假设肺炎中 C5a 浓度增加，C5a 中和可促进肺屏障稳定，并对肺炎球菌性肺脓毒症具有保护作用。
作者在一项前瞻性患者队列研究和实验性肺炎中研究了肺炎中 C5a 的调节。应用了两种互补的小鼠肺炎球菌性肺炎模型。用 C5a 中和 L-RNA-适体 NOX-D19 处理雌性小鼠。通过测量肺通透性（主要结局）、肺和血液白细胞、肺和血液中细胞因子浓度、肺、脾脏和血液中的细菌负荷以及进行组织损伤、细胞凋亡和纤维蛋白沉积的组织学分析来评估肺、肝和肾损伤和炎症反应（n = 5 至 13）。
与健康受试者（n = 24；中位数 [25%至 75% 四分位距] 4.5 nmol/L [3.8 至 6.6]）相比，患有肺炎的住院患者（n = 395）血清 C5a 浓度更高（6.3 nmol/L [3.9 至 10.0]；差异：1.4 [95%置信区间，0.1 至 2.9]；P = 0.029）。在肺炎球菌性肺炎或合并严重肺炎和机械通气中，C5a 的中和导致肺通透性降低（1.38 ± 0.89 与 3.29 ± 2.34，均值 ± 标准差；差异：1.90 [95%置信区间，0.15 至 3.66]；P = 0.035；n = 10 或 11）或合并严重肺炎和机械通气（2.56 ± 1.17 与 7.31 ± 5.22；差异：4.76 [95%置信区间，1.22 至 8.30]；P = 0.011；n = 9 或 10）。此外，C5a 中和导致血液粒细胞集落刺激因子浓度降低，并防止脓毒症相关肝损伤。
肺炎患者中循环 C5a 升高。在小鼠肺炎球菌性肺炎中，C5a 的中和可预防肺和肝损伤。早期 C5a 中和可能是改善社区获得性肺炎结局的一种有前途的辅助治疗策略。
