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Surfactant plays an important role in lung homeostasis and is also involved in maintaining innate immunity within the lung. Lipopolysaccharide (LPS) from gram-negative bacteria is known to elicit acute proinflammatory responses in lung diseases such as acute respiratory distress syndrome and pneumonia, among others. Our previous studies demonstrated that the clinically used, natural surfactant product Survanta inhibited proinflammatory cytokine secretion from LPS-stimulated human alveolar macrophages. Here we investigated the effect of Survanta on mitogen-activated protein (MAP) and IκB kinases. Survanta blocked LPS-induced activation of nuclear factor-κB, a key regulatory transcription factor involved in cytokine production, by preventing phosphorylation of IκBα, and its subsequent degradation. IκB is phosphorylated by specific kinases (IKK) before degradation. Survanta inhibited activity of both α and β subunits of IKK, thereby delaying the phosphorylation of IκB. Interestingly, IKK-α is predominant in alveolar macrophages, whereas IKK-β predominates in monocytes. Survanta also inhibited extracellular signal-regulated kinase and p38 MAP kinase activity induced by LPS. Data are the first to show that surfactant may regulate lung homeostasis in part by inhibiting proinflammatory cytokine production through reduction of IKK and MAP kinase activity.