Epithelial laminin α5 is necessary for distal epithelial cell maturation, VEGF production, and alveolization in the developing murine lung

Laminin alpha 5 is prominent in the basement membrane of alveolar walls, airways, and pleura in developing and adult lung. Targeted deletion of laminin alpha 5 in mice causes developmental defects in multiple organs, but embryonic lethality has precluded examination of the latter stages of lung development. To identify roles for laminin alpha 5 in lung development, we have generated an inducible lung epithelial cell-specific Lama5 null (SP-CLama5(fl/-)) mouse through use of the Cre/loxP system, the human surfactant protein C promoter, and the reverse tetracycline transactivator. SP-CLama5(fl/-) embryos exposed to doxycycline from E6.5 died a few hours after birth. Compared to control littermates, SP-CLama5(fl/-) lungs had dilated, enlarged distal airspaces, but basement membrane ultrastructure was preserved. Distal epithelial cell differentiation was perturbed, with a marked reduction of alveolar type II cells and a virtual absence of type I cells. Cell proliferation was reduced and apoptosis was increased. Capillary density was diminished, and this was associated with a decrease in total lung VEGF production. Overall, these findings indicate that epithelial laminin alpha 5, independent of its structural function, is necessary for murine lung development, and suggest a role for laminin alpha 5 in signaling pathways that promote alveolar epithelial cell differentiation and VEGF expression. (c) 2005 Elsevier Inc. All rights reserved.