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Lung development is a highly regulated process directed by mesenchymal-epithelial interactions, which coordinate the temporal and spatial expression of multiple regulatory factors required for proper lung formation. The Iroquois homeobox (Irx) genes have been implicated in the patterning and specification of several Drosophila and vertebrate organs, including the heart. Herein, we investigated whether the Irx genes play a role in lung morphogenesis. We found that Irx1-3 and Irx5 expression was confined to the branching lung epithelium, whereas Irx4 was not expressed in the developing lung. Antisense knockdown of all pulmonary Irx genes together dramatically decreased distal branching morphogenesis and increased distention of the proximal tubules in vitro, which was accompanied by a reduction in surfactant protein C-positive epithelial cells and an increase in [beta]-tubulin IV and Clara cell secretory protein positive epithelial structures. Transmission electron microscopy confirmed the proximal phenotype of the epithelial structures. Furthermore, antisense Irx knockdown resulted in loss of lung mesenchyme and abnormal smooth muscle cell formation. Expression of fibroblast growth factors (FGF) 1, 7, and 10, FGF receptor 2, bone morphogenetic protein 4, and Sonic hedgehog (Shh) were not altered in lung explants treated with antisense Irx oligonucleotides. All four Irx genes were expressed in Shh- and Gliz-deficient murine lungs. Collectively, these results suggest that Irx genes are involved in the regulation of proximo-distal morphogenesis of the developing lung but are likely not linked to the FGF, BMP, or Shh signaling pathways. Iroquois homeobox genes; differentiation; sonic hedgehog; fibroblast growth factor; bone morphogenic protein 4

Hyperoxic exposure enhances the synthesis of insulin-like growth factor (IGF) and its type I receptor in the lungs of adult rats. The expression of growth-stimulating and growth-inhibiting insulin-like growth factor binding proteins (IGFBPs) was investigated to determine if their expression is consistent with the observed synthesis of IGF. Results reveal the most of the IGFBPs generally follow the modulation of IGF synthesis.

Rat lungs exposed to 85% oxygen showed a significant increase in insulin-like growth factor I (IGF-I) mRNA and peptide after 6 and 14 days of exposure, with maximal expression in the airway and alveolar epithelium. IGF-receptor immunoreactivity (IGFR) also showed a significant increase 6 days after exposure andd localized to the perivascular, peribronchial and endothelial cells. At 14 days after exposure, IGFR localized to the alveolar epithelial cells.

An initial loss of type I pneumocytes is exhibited by lungs subjected to the exposure of increased oxygen exposure. These lungs also exhibit a loss of reparative type II pneumocyte hyperlasia. These losses are primarily caused by the elevation in the concentration of intrapulmonary basic fibroblast growth factor (bFGF). The bFGF is a powerful stimulator of type II pneumocyte DNA synthesis.

Variation in the proteinase antiproteinase balance in the lung leads to an enhancement of type I collagen deposition, which is induced by oxygen exposure. The deposition of type I collagen is optimum after 14 days of exposure to 85% oxygen. There is an increase in the mRNA expression of interstitial collagenase, the tissue inhibitor of metalloproteinases and the transforming growth factor-beta1 prior to type I collagen increase. There are no variations in the mRNA expression of stromelysin.