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The aim of the present study was to examine the role of the actin cytoskeleton in regulating the expulsion of NETs. Actin-related protein 2\/3 (Arp 2\/3) complex is an important regulator of F-actin polymerization. Coincubation with CK666, a specific Arp 2\/3 inhibitor, decreased 12-phorbol 13-myristate acetate-induced NET formation in vitro. CK666 not only abolished F-actin polymerization but also caused intracellular retention of NETs. Inhibition of Arp 2\/3 reduced NET formation on circulating neutrophils and in the bronchoalveolar space in mice undergoing cecal ligation and puncture (CLP). Notably, treatment with CK666 attenuated CLP-induced neutrophil recruitment, edema formation, and tissue damage in the lungs. Moreover, Arp 2\/3 inhibition decreased levels of C-X-C motif chemokine ligand 1 (CXCL-1) and interleukin-6 in the lung and plasma of septic animals. 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