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

Previously, we used a nonhuman primate model to show that C5a is an effective target for treatment of ALI induced by viral infection (11) . However, little is known about the role of aberrant complement activation in paraquat-induced ALI. Here, we established a cynomolgus macaque model of paraquat-induced ALI to better understand the role of complement and to identify therapeutic targets. After paraquat administration, the monkeys showed typical ALI characteristics, including scattered hyperemia, thickened alveolar septa, and infiltration of inflammatory cells accompanied by cellular degeneration and/or necrosis (Supplemental Fig. 2A , Supplemental Digital Content 4, http:// links.lww.com/CCM/D162; legend, Supplemental Digital Content 1, http://links.lww.com/CCM/D159). At 6 hours, after paraquat administration, the serum concentrations of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, IP-10, and MCP-1 were marked higher than those in control animals (Supplemental Fig. 2B , Supplemental Digital Content 4, http:// links.lww.com/CCM/D162; legend, Supplemental Digital Content 1, http://links.lww.com/CCM/D159). The concentration of C3a, C5a, and C5b-9, indicators of complement activation, was also significantly higher in paraquat-treated animals at the same time point (Supplemental Fig. 3A , Supplemental Digital Content 5, http://links.lww.com/CCM/D163; legend, Supplemental Digital Content 1, http://links.lww.com/CCM/D159). Paraquat up-regulated expression of C3aR and C5aR in lung tissues relative to that in normal lung tissues. Deposition of C3c was greater in lung tissues from paraquat-treated animals than in those from untreated animals (Supplemental Fig. 3B , Supplemental Digital Content 5, http://links.lww.com/CCM/D163; legend, Supplemental Digital Content 1, http://links.lww.com/ CCM/D159). Taken together, these data further support aberrant activation of the complement system. One may argue that the route of administration of paraquat to macaques is different from that to the patients with paraquat poisoning as mentioned above. Because of the difficulty to control the amount of paraquat applied orally due to the severe vomit, we had to administer paraquat intraperitoneally according to the dynamic distribution and absorption of paraquat (30, 31) and obtained reproducible results which consistent with those from testing the blood samples of the patients with paraquat poisoning.