Serum amyloid A3 confers protection against acute lung injury in Pseudomonas aeruginosainfected mice. Am J Physiol Lung Cell Mol Physiol 318: L314-L322, 2020. First published December 18, 2019; doi:10.1152/ajplung. 00309.2019.-Pseudomonas aeruginosa is a gram-negative bacterium associated with serious illnesses, including ventilator-associated pneumonia and various sepsis syndromes in humans. Understanding the host immune mechanisms against P. aeruginosa is, therefore, of clinical importance. The present study identified serum amyloid A3 (SAA3) as being highly inducible in mouse bronchial epithelium following P. aeruginosa infection. Genetic deletion of Saa3 rendered mice more susceptible to P. aeruginosa infection with decreased neutrophil superoxide anion production, and ex vivo treatment of mouse neutrophils with recombinant SAA3 restored the ability of neutrophils to produce superoxide anions. The SAA3-deficient mice showed exacerbated inflammatory responses, which was characterized by pronounced neutrophil infiltration, elevated expression of TNF-_, KC/CXCL1, and MIP-2/CXCL2 in bronchoalveolar lavage fluid (BALF), and increased lung microvascular permeability compared with their wild-type littermates. BALF neutrophils from Saa3 knockout mice exhibited reduced superoxide anion production compared with neutrophils from wild-type mice. Adoptive transfer of SAA3-treated neutrophils to Saa3 knockout mice ameliorated P. aeruginosainduced acute lung injury. These findings demonstrate that SAA3 not only serves as a biomarker for infection and inflammation, but also plays a protective role against P. aeruginosa infection-induced lung injury in part through augmentation of neutrophil bactericidal functions.