Primary lung fibroblasts treated with hedgehog agonist, purmorphamine

Postnatal tissue quiescence is generally thought to be a default state in the absence of a proliferative stimulus such as injury. We now demonstrate that in the lung, quiescence in the adult is an actively maintained state and is regulated by paracrine hedgehog signaling. Epithelial-specific deletion of Sonic Hedgehog during normal homeostasis results in a proliferative expansion of the adjacent lung mesenchyme. Injury to the lung epithelium results in decreased hedgehog activation, accompanied by proliferative expansion of the adjacent mesenchyme. Moreover, reconstitution of Hedgehog signaling during epithelial injury attenuated the proliferative expansion of the adjacent mesenchyme. Hedgehog signaling maintains lung quiescence by attenuating PDGF signaling through blocking post-translational processing of PDGF receptor α/β into the mature isoforms. These results indicate that in postnatal tissues, epithelial cells can actively maintain mesenchymal quiescence via paracrine hedgehog activation, and that imbalances in this pathway could lead to aberrant mesenchymal expansion and postnatal disease. Fibroblasts were isolated from mouse lungs and grown in culture in triplicate wells. Samples were treated with vehicle or purmorphamine 5um for 24 hours and RNA was isolated for microarray.