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Integrin 6 Mediates Phospholipid and Collectin Homeostasis by Activation of Latent TGF-1

¹ Lung Biology Center, Department of Medicine, San Francisco General Hospital, and ² Department of Pediatrics, University of California, San Francisco, San Francisco, California; and ³ Section of Pulmonary and Critical Care Medicine, Department of Medicine, Yale School of Medicine, New Haven, Connecticut

Correspondence and requests for reprints should be addressed to Laura Koth, University of California, San Francisco, Mission Bay, Rock Hall, Box 2922, San Francisco, CA 94158. E-mail: Laura.Koth{at}ucsf.edu

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 postnatal lung is poorly understood. We found that the epithelial integrin, v6, regulates surfactant homeostasis in vivo by activating latent transforming growth factor (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 TGF-1 in Itgb6^–/– mice, we found that TGF-1 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 TGF-1 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-1 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.

Key Words: surfactant • macrophage • lung • integrin • transforming growth factor-

CLINICAL RELEVANCE Our findings may have significant implications for the treatment of fibrotic lung diseases, such as idiopathic pulmonary fibrosis, that target transforming growth factor- in the lung. Our work also identifies mediators that may have relevance to human disorders of surfactant dysregulation.

 

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