Beta 1 Integrin in the Lung

Vanderbilt University Medical Center, Nashville TN

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Abstract

? DESCRIPTION (provided by applicant): Proper organogenesis requires assimilation of microenvironmental cues from the extracellular matrix (ECM). Integrins mediate epithelial cell-ECM interactions in branched organs and guide coordinated epithelial cell proliferation, migration, and differentiation, processes critical for development and repair after injury. Congenital integrin mutations result in kidney, mammary, and submandibular gland hypoplasia and, in the kidney, also modulate the fibrotic response to injury. Recently, disrupted cell-ECM interactions due to integrin a3 subunit mutations have been shown to cause lung hypoplasia/dysplasia in humans. However, very little is known about how cell-ECM interactions regulate lung development and repair. Most of our knowledge about cell-ECM interactions in the lung is based on the study of laminins, critical components of the lung basement membrane. Transgenic murine models clearly demonstrate that specific laminin chains are required for lung branching morphogenesis and human mutations in the laminin a2, a5, and ß1 genes are associated with lung disease. Integrins, which are comprised of an a and ß subunit, form the principal laminin and collagen receptors in the lung with the ß1 subunit being the common subunit in these receptors. Deleting ß1 removes nearly all the ECM receptors from the lung epithelium. We recently deleted ß1 integrin specifically in the murine lung epithelium at E10.5, P0, and P28 to investigate the role of cell-ECM interactions during lung development. Loss of ß1 integrin at E10.5 impaired both branching morphogenesis and alveolarization. Deleting ß1 integrin at P0 resulted in only an alveolarization defect and deletion of ß1 integrin at P28, afte the completion of alveolarization, resulted in normal lungs but increased susceptibility to mechanical stress-induced injury. These findings indicate that epithelial ß1 integrin plays distint roles during both alveolarization and post-development. One of our key findings was that epithelial ß1 integrin regulated septation, epithelial differentiation and macrophage infiltration during alveolarization. Further in vitro studies with ß1 integrin null epithelial cells suggested hat ß1 regulated macrophage accumulation by increasing production of reactive oxygen species and monocyte chemoattractant protein-1, the main chemoattractant for lung macrophages. The mechanisms whereby ß1 integrin expression regulates the fundamental processes required for normal alveolarization and homeostasis are unknown. In this grant we will use our novel model of temporal deletion of lung epithelial ß1 integrin to test the hypothesis that epithelial ß1 intgrin regulates secondary septation during early alveolarization and maintains alveolar homeostasis in the adult lung by regulating lung inflammation and epithelial differentiation. AIM 1. Determine the mechanism whereby ß1 integrin-dependent cell-ECM interactions regulate secondary septation. AIM 2. Determine the mechanism whereby epithelial ß1 integrin is required for alveolar homeostasis.