Interleukin (IL)-18 belongs to a rather large IL-1 gene family and is a proinflammatory cytokine. IL-18 plays important roles in lung injury. IL-18 binding protein (IL-18BP), a natural antagonist of IL-18, binds IL-18 with high affinity. IL-18BP is able to neutralize IL-18 biological activity and has a protective effect against renal fibrosis. The aim of this study was to evaluate the potential protective effect of IL-18BP on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and to illuminate the underlying mechanisms. Results indicated that pretreatment with IL-18BP significantly attenuated LPS-induced pulmonary pathological injury. Meanwhile, IL-18BP pretreatment markedly inhibited infiltration of inflammatory cell and release of inflammatory factor in ALI mice in vivo and in primary macrophages after LPS insult in vitro. IL-18BP treatment dramatically reduced oxidative stress through increasing superoxide dismutase (SOD) and glutathione (GSH) contents, and decreasing the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) in LPS-induced ALI mice and primary macrophages. Additionally, IL-18BP was also observed to markedly decreased the activation of nuclear factor kappa B (NF-kappa B) and upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, IL-18BP possessed protective effect against LPS-induced ALI, which might be associated with its regulation of NF-kappa B and Nrf2 activities. The results rendered IL-18BP worthy of further development into a pharmaceutical drug for the treatment of ALI. (C) 2018 Elsevier Inc. All rights reserved.