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

The complement system is a key upstream sensor and effector system whose activation products are important regulators of immunologic and inflammatory processes; however, they also participate in many diseases and disorders (1). C5a is a major anaphylatoxin and exerts strong proinflammatory effects by targeting a broad spectrum of immune and nonimmune cells, affecting the migration of macrophages and neutrophils, and inducing synthesis of other chemotactic factors (2, 24) . Furthermore, C5a triggers an oxidative burst in macrophages, neutrophils, and eosinophils and increases TNF-α and IL-1β gene expression and protein synthesis by macrophages (39) . In a previous study, we showed that IFX-1 reduced serum levels of TNF-α, IL-1β, and IL-6 in African Green Monkeys infected with H7N9 virus (11) . Here, we used a monkey model of paraquat-induced ALI to show that IFX-1 reduced the number of inflammatory cell infiltrating in lung, as well as levels of CRP, BUN, ALT and IL-1β, TNF-α, IL-6, thereby reducing injury to the lung, spleen, kidney, and intestine. Altered permeability of the alveolar endothelial and epithelial barriers remains a central pathophysiologic event in ALI. Indeed, the pulmonary endothelium plays a key role in the development of ALI (40, 41) . Once activated, endothelial cells secrete cytokines and chemokines such as TNF-α, IL-1β, and MCP-1, which recruit neutrophils and macrophages and contribute to collateral cell damage and organ dysfunction. Zeng et al (42) demonstrated that H5N1-induced damage to pulmonary endothelial cells triggered host inflammatory responses and that C5a may participate in endothelial activation and affect expression of adhesion molecules. We found that IFX-1 increased VE-cadherin expression and alleviated lung lesions, suggesting that decreased activation of endothelial cells and an improved endothelial barrier in the lung contribute to an improved outcome. IFX-1 may also preserve lung function, as evidenced by the increased SP-A level in treated animals. SP-A is closely associated with lung structure and innate immune responses. It is unclear whether alveolar epithelial injury is primary to paraquat insult or secondary to lung endothelial injury. Nonetheless, it is evident that damage to epithelial and endothelial cells converges on a common pathway, resulting in diffuse alveolar damage. As such, reduced endothelial activation and protection of lung epithelial cells may be a potential mechanism underlying C5a blockade.