Regulated stimulation of epithelial cell DNA synthesis by fibroblast-derived mediators

Interactions of interstitial fibroblasts with nearby epithelial cells are thought to play a role in lung growth and development. The present studies support this premise. Medium conditioned by second-passage lung fibroblasts (FCM) stimulated both DNA synthesis and accumulation in low-density (2 x 10(4)/cm2) cultures of type II alveolar epithelial cells. FCM effects did not require serum; they were time- and dose dependent, with half-maximal FCM activity at 1:8 dilution. A maximal response to FCM required 30 h of exposure. FCM activity was reduced in medium from fibroblasts treated with dexamethasone, suggesting physiological regulation. Type II cells subjected to cyclic mechanical stress demonstrated an increased response to FCM compared with static cultures. FCM activity did not appear to be accounted for by hepatocyte growth factor, keratinocyte growth factor, acidic fibroblast growth factor, or fibronectin. These results suggest that early passage lung fibroblasts release, by regulated pathways, one or more factors that stimulate DNA synthesis by type II cells. Sensitivity to FCM appears to be elevated in type II cell cultures subjected to cyclic mechanical stress.