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

Gross necropsy at 16 hours post paraquat administration revealed that the lungs of cynomolgus macaques in the sham treatment group were cardinal red, whereas the lungs of cynomolgus macaques receiving IFX-1 were a lighter shade (Fig. 4A) . Microscopic observation of lungs from shamtreated cynomolgus macaques at 16 hours post paraquat administration showed hemorrhagic alveolar damage characterized by scattered hyperemia, thickened alveolar septa, and infiltration by moderate numbers of neutrophils and macrophages, and degeneration or necrosis of the alveolar epithelium, with vacuolization of pneumocytes or with karyorrhexis and loss of cellular detail. Less exudation and some foamy alveolar macrophages and scattered neutrophils and erythrocytes were also observed in the alveolar lumen. However, the lungs of IFX-1-treated animals showed less severe damage, with some thickening of alveolar septa (Fig. 4B; and Supplemental Fig. 6 SP-A is a pulmonary surfactant primarily responsible for reducing surface tension at the air-liquid interface in the alveoli and plays an important role in the innate host defense and regulation of the inflammatory process in the lung (34) . To further study the effect of IFX-1 on injury to the lung parenchyma, we examined expression of SP-A by immunohistochemistry. IFX-1 treatment increased expression of SP-A, suggesting that it may help protect alveolar epithelial cells (Fig. 4B ). In addition, the expression and transcription level of VE-cadherin, a molecule important for maintaining endothelial barrier integrity in lung microvessels (35) , increased significantly at 16 hours post IFX-1 treatment (p < 0.01), further confirming that anti-C5a treatment protects lung integrity and function during paraquat-induced ALI (Supplemental Fig. 6 , A and C, Supplemental Digital Content 8, http://links. lww.com/CCM/D166; legend, Supplemental Digital Content 1, http://links.lww.com/CCM/ D159). In addition, anti-C5a treatment also effectively ameliorated damage to organs including the spleen (Supplemental Fig. 7 , Supplemental Digital Content 9, http://links.lww.com/CCM/ D167; legend, Supplemental Digital Content 1, http://links. lww.com/CCM/D159), kidney, and intestine (Supplemental