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

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. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Drs. Sun, Jiang, and Wang contributed equally to this work. Drs. Qiu, Zhao, and Zhou had full access to all of the data reported in this study and had final responsibility for the decision to submit this report for publication. Drs. Sun, Wang, Li, Zhao, and Zhou designed research study; Drs. Sun, Jiang, Wang, C. Liu, X. Liu, Song, and Guo performed research; Drs. Sun, Jiang, Wang, Li, and Zhao analyzed data; Drs. Sun, Zhao, and Zhou wrote the article; and Drs. Wang, Guo, Du, Jiang, and Li for revising the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Supported, in part, by grants from the National Nature Science Foundation of China (81571983 and 81371805), the Program of National Ministry of Science and Technology (2014ZX09J14105-04B) and funding of State Key Laboratory of Pathogen and Biosecurity (SKLPBS1509). Dr. R. Guo disclosed that he is a cofounder for InflaRx, who provides IFX-1 used in this study. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: qiuzw828@163.com; guangyu0525@163.com; yszhou@bmi.ac.cn Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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