Surfactant lines the alveolar surface and prevents alveolar collapse. Derangements of surfactant cause respiratory failure and interstitial lung diseases. The collectins, surfactant proteins A and D, are also important in innate host defense. However, surfactant regulation in the post-natal lung is poorly understood. We found that the epithelial integrin, v6, regulates surfactant homeostasis in vivo by activating latent TGF. Adult mice lacking the -subunit of v6 (Itgb6^-/-) developed increased bronchoalveolar lavage phospholipids and surfactant proteins A and D and demonstrated abnormal appearing alveolar macrophages, reminiscent of the human disease pulmonary alveolar proteinosis. Using lung-specific expression of constitutively active TGF1 in Itgb6^-/- mice we found that TGF1 was sufficient to normalize these abnormalities. Tgf1-deficient mice also demonstrated increased phospholipids and surfactant proteins A and D but mice lacking the key TGF signaling molecule, SMAD3, did not. Therefore, integrin-mediated activation of latent TGF1 regulates surfactant constituents independent of intracellular SMAD3. In vivo increases in surfactant protein A and D were not associated with increases in mRNA for these proteins in alveolar tissue from Itgb6^-/- mice. On the other hand, isolated alveolar macrophages from Itgb6^-/- mice were defective in processing phospholipids in vitro, suggesting that reduced surfactant clearance contributes to altered surfactant homeostasis in these mice in vivo. These findings show that v6 and TGF regulate homeostasis of phospholipids and collectins in adult mouse lungs and may have implications for anti-fibrotic therapeutics that inhibit active TGF in the lung.