Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization.
Integrin-dependent interactions between cells and extracellular matrix regulate lung development; however, specific roles for β1-containing integrins in individual cell types, including epithelial cells, remain incompletely understood. In this study, the functional importance of β1 integrin in lung epithelium during mouse lung development was investigated by deleting the integrin from E10.5 onwards using surfactant protein C promoter-driven Cre. These mutant mice appeared normal at birth but failed to gain weight appropriately and died by 4 months of age with severe hypoxemia. Defects in airway branching morphogenesis in association with impaired epithelial cell adhesion and migration, as well as alveolarization defects and persistent macrophage-mediated inflammation were identified. Using an inducible system to delete β1 integrin after completion of airway branching, we showed that alveolarization defects, characterized by disrupted secondary septation, abnormal alveolar epithelial cell differentiation, excessive collagen I and elastin deposition, and hypercellularity of the mesenchyme occurred independently of airway branching defects. By depleting macrophages using liposomal clodronate, we found that alveolarization defects were secondary to persistent alveolar inflammation. β1 integrin-deficient alveolar epithelial cells produced excessive monocyte chemoattractant protein 1 and reactive oxygen species, suggesting a direct role for β1 integrin in regulating alveolar homeostasis. Taken together, these studies define distinct functions of epithelial β1 integrin during both early and late lung development that affect airway branching morphogenesis, epithelial cell differentiation, alveolar septation and regulation of alveolar homeostasis.
Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Erin J
EJ
Plosa
Department of Pediatrics, Division of Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Lisa R
LR
Young
Department of Pediatrics, Division of Pulmonary Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Peter M
PM
Gulleman
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Vasiliy V
VV
Polosukhin
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Rinat
R
Zaynagetdinov
Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
John T
JT
Benjamin
Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Amanda M
AM
Im
Department of Pediatrics, Division of Neonatology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Riet
R
van der Meer
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Linda A
LA
Gleaves
Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Nada
N
Bulus
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Wei
W
Han
Department of Pediatrics, Division of Neonatology, University of California San Diego, San Diego, CA 92103, USA.
Lawrence S
LS
Prince
Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Nashville Veterans Affairs Medical Center, Nashville, TN 37232, USA.
Timothy S
TS
Blackwell
Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA Nashville Veterans Affairs Medical Center, Nashville, TN 37232, USA roy.zent@vanderbilt.edu.
Roy
R
Zent
D000818:Animals; D018893:Bronchoalveolar Lavage; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D019012:Integrin beta1 / Q000378:metabolism*; D008168:Lung / Q000196:embryology*; D051379:Mice; D018613:Microscopy, Confocal; D038081:Organogenesis / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000196:embryology*; D037721:Pulmonary Surfactant-Associated Protein C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances
D018932:Chemokine CCL2; D019012:Integrin beta1; D037721:Pulmonary Surfactant-Associated Protein C; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; C045073:Cre recombinase; D019426:Integrases
Alveolar epithelial cell; Branching morphogenesis; Differentiation; Extracellular matrix; Inflammation; Reactive oxygen species