Treatment of Paraquat-Induced Lung Injury With an Anti-C5a Antibody: Potential Clinical Application*

Sun, Shihui; Jiang, Yuting; Wang, Renxi; Liu, Chenfeng; Liu, Xiaoling; Song, Nianping; Guo, Yan; Guo, Renfeng; Du, Lanying; Jiang, Shibo; Li, Yan; Qiu, Zewu; Zhao, Guangyu; Zhou, Yusen

OBJECTIVES: 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. DESIGN: Study of cynomolgus macaque model and plasma from paraquat-poisoning patients. SETTING: Laboratory investigation. SUBJECTS: Cynomolgus macaque (n = 12) and samples of plasma from patients (n = 16). INTERVENTIONS: 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. MEASUREMENTS AND MAIN RESULTS: 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. CONCLUSIONS: 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.