title: Integrin beta6 mediates phospholipid and collectin homeostasis by activation of latent TGF-beta1.
abstract: 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, alphavbeta6, regulates surfactant homeostasis in vivo by activating latent transforming growth factor (TGF)-beta. Adult mice lacking the beta-subunit of alphavbeta6 (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-beta1 in Itgb6-/- mice, we found that TGF-beta1 was sufficient to normalize these abnormalities. Tgfbeta1-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-beta1 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 alphavbeta6 and TGF-beta1 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.
authors.affiliation: Lung Biology Center, Department of Medicine, San Francisco General Hospital, California, USA. Laura.Koth@ucsf.edu
authors.forename: Laura L
authors.initials: LL
authors.lastname: Koth
authors.forename: Byron
authors.initials: B
authors.lastname: Alex
authors.forename: Samuel
authors.initials: S
authors.lastname: Hawgood
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nead
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: David J
authors.initials: DJ
authors.lastname: Erle
authors.forename: David G
authors.initials: DG
authors.lastname: Morris
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002469:Cell Separation; D037222:Collectins / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D039641:Integrin beta Chains / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D010743:Phospholipids / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011663:Pulmonary Surfactants / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D037222:Collectins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D039641:Integrin beta Chains; D010743:Phospholipids; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D011663:Pulmonary Surfactants; D051900:Smad3 Protein; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D000099232:Proto-Oncogene Protein Spi-1; C072170:integrin beta6