State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Laboratory of Immunology, Beijing Institute of Basic Medical Sciences, Beijing, China.
Crit Care Med. 2018 May;46(5):e419-e425. doi: 10.1097/CCM.0000000000002950.
Complement activation product C5a plays a critical role in systemic inflammatory response syndrome induced by viruses, bacteria, and toxic agents including paraquat poisoning. This study is to explore the efficiency of anti-C5a-based intervention on systemic inflammatory responses induced by paraquat poisoning.
Study of cynomolgus macaque model and plasma from paraquat-poisoning patients.
Laboratory investigation.
Cynomolgus macaque (n = 12) and samples of plasma from patients (n = 16).
The neutralizing antihuman C5a antibody (IFX-1) was administered to investigate the new treatment strategy for paraquat-induced systemic inflammatory responses in cynomolgus macaque model. In addition, C5a activation in plasma of paraquat patients was blocked by IFX-1 to investigate the blockade role of anti-C5a antibody in activation of inflammatory cells.
Dysregulated complement activation and the subsequent cytokine storm were found in patients with acute lung injury and in a primate model of paraquat poisoning. Targeted inhibition of C5a by IFX-1 led to marked alleviation of systemic inflammatory responses and multiple organ damage in the primate model. In addition, blockade of C5a activity in plasma from patients completely inhibited activation of CD11b on blood granulocytes from normal donors, suggesting that IFX-1 may alleviate the excessive activation of inflammatory responses and have clinical utility for patients with acute lung injury.
Anti-C5a antibodies such as IFX-1 may be used as effective therapeutics for treatment of those suffering from systemic inflammatory responses induced by chemical poisoning like paraquat.
补体激活产物 C5a 在病毒、细菌和包括百草枯中毒在内的毒性物质引起的全身炎症反应综合征中发挥关键作用。本研究旨在探讨基于抗 C5a 的干预措施对百草枯中毒引起的全身炎症反应的疗效。
恒河猴模型和百草枯中毒患者血浆研究。
实验室研究。
恒河猴（n=12）和百草枯中毒患者的血浆样本（n=16）。
给予中和抗人 C5a 抗体（IFX-1），以研究针对恒河猴模型百草枯诱导的全身炎症反应的新治疗策略。此外，通过 IFX-1 阻断百草枯患者血浆中 C5a 的激活，研究抗 C5a 抗体在激活炎症细胞中的阻断作用。
在急性肺损伤患者和百草枯中毒的灵长类动物模型中发现失调的补体激活和随后的细胞因子风暴。通过 IFX-1 靶向抑制 C5a 可显著减轻灵长类动物模型中的全身炎症反应和多器官损伤。此外，在来自正常供体的血液粒细胞上完全抑制 C5a 活性的患者血浆中阻断 C5a 活性，提示 IFX-1 可能减轻炎症反应的过度激活，并对急性肺损伤患者具有临床应用价值。
抗 C5a 抗体（如 IFX-1）可作为治疗化学中毒（如百草枯）引起的全身炎症反应的有效治疗药物。
