Persistent versus transient map kinase (ERK) activation in the proliferation of lung epithelial type 2 cells

Type 2 pneumocytes are progenitor cells of alveolar epithelium and important for re-epithelialization following lung injury. This study examined the role of persistent versus transient mitogen-activated protein (MAP) kinase (extracellular signal-regulated kinase; ERK) in type 2 cell proliferation. Three different types of agents; epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate (TPA), and fetal bovine serum (FBS) induced different patterns of ERK activation. FBS induced a strong and persistent MAP kinase response, whereas the effects of EGF was transient with a strong activation at 5 minutes and only a slight stimulation at 4 hours. The TPA response was more prolonged than the EGF response, but not by far as strong and persistent as the FBS response. Activation by EGF and TPA and the early response induced by FBS were strongly reduced by the MEK inhibitor PD98059. The sustained FBS-induced ERK activation was inhibited by similar to 50%. The total number of cells, the percentage of cells in S and G(2)/M phase of the cell cycle and the incorporation of H-3-thymidine into DNA were strongly increased in response to FBS, whereas EGF and TPA were without effect. The proliferation was reduced by similar to 50% after pretreatment with PD98059. The results indicate that a persistent ERK activation of a critical size leads to type 2 cell proliferation, and that thr proliferative response may also depend un a MEK-independent ERK activation.