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Published ahead of print on July 19, 2007, doi:10.1165/rcmb.2006-0428OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 6, December 2007, 651-659

A more recent version of this article appeared on December 1, 2007
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Submitted on November 16, 2006
Revised on July 17, 2007

Integrin {beta}6 Mediates Phospholipid and Collectin Homeostasis by Activation of Latent TGF{beta}1

Laura L Koth1*, Byron T Alex1, Samuel Hawgood2, Michael A Nead3, Dean Sheppard1, David J Erle1, and David G Morris3

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

* To whom correspondence should be addressed. 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 post-natal lung is poorly understood. We found that the epithelial integrin, {alpha}v{beta}6, regulates surfactant homeostasis in vivo by activating latent TGF{beta}. Adult mice lacking the {beta}-subunit of {alpha}v{beta}6 (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{beta}1 in Itgb6-/- mice we found that TGF{beta}1 was sufficient to normalize these abnormalities. Tgf{beta}1-deficient mice also demonstrated increased phospholipids and surfactant proteins A and D but mice lacking the key TGF{beta} signaling molecule, SMAD3, did not. Therefore, integrin-mediated activation of latent TGF{beta}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 {alpha}v{beta}6 and TGF{beta} regulate homeostasis of phospholipids and collectins in adult mouse lungs and may have implications for anti-fibrotic therapeutics that inhibit active TGF{beta} in the lung.




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