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A2983 - A Phagocyte-Targeted Toll-Like Receptor Nano-Inhibitor Protects Mice Against Lipopolysaccharide-Induced Acute Lung Injury
Author Block: Y. Xiong1, H. Yang2, Q. Li2; 1Changhai Hospital, Shanghai, China, 2Shanghai General Hospital, Shanghai, China.
Toll like receptors (TLRs) plays a crucial role in the pathogenesis of acute respiratory distress syndrome (ARDS) or its milder form of acute lung injury (ALI). Manipulation of TLR mediated inflammatory responses using nano-devices provides a new therapeutic strategy to treat ARDS/ALI. Previously, we developed a novel class of peptide-gold nanoparticle hybrids with programmable inhibitory activities on multiple TLR signaling pathways in macrophages. In this study, we first demonstrated that the TLR nano-inhibitor P12 could primarily target phagocytes including monocytes and macrophages to dampen TLR4 signaling in vitro. We then investigated the in vivo efficacy of the nano-inhibitor in a lipopolysaccharide (LPS)-induced murine model of ALI. It was found that P12 was mainly taken up by phagocytes in the lung after intratracheal instillation, and effectively reduced LPS-induced acute lung inflammation and injury. Specifically, P12 decreased neutrophil infiltration and increased the number of Treg in the lung. In addition, we studied the biodistribution and metabolic paths of the peptide-gold nanoparticle hybrids. It was found that 26 h after administration, only about 10% nanoparticles remained in the body, and majority of them were distributed in the lung and intestine, suggesting that the nanoparticles were likely excreted out through digestive tracts. This work provides the in vivo evidences of the novel TLR nano-inhibitor P12 in reducing the excessive inflammation of ALI, representing the next generation targeted anti-inflammatory therapy to treat ARDS.