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Conditional deletion of Stat-3 in respiratory epithelial cells in the lung of transgenic mice ( Stat-3<jats:sup>\u0394\/\u0394<\/jats:sup>mice) decreased surfactant phospholipid synthesis and secretion. Deletion of Stat-3 was associated with decreased expression of Akt2, Srebf-1, and other genes expressed in type II cells that may influence surfactant phospholipid synthesis ( Glut-1, Slc34a2, Gpam, Acox2, and Cds2). Stat-3<jats:sup>\u0394\/\u0394<\/jats:sup>mice were more susceptible to intratracheal lipopolysaccharide (LPS). Saturated phosphatidylcholine and surfactant protein B levels were significantly decreased in bronchoalveolar lavage fluid from LPS-treated Stat-3<jats:sup>\u0394\/\u0394<\/jats:sup>mice. Alveolar capillary leak, proinflammatory cytokine expression, and perturbations of lung mechanics caused by LPS were exacerbated after deletion of STAT-3. 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