Alveolar type II epithelial cells are the main precursor cells that develop into carcinomas after inhalation of poorly soluble particles (PSP) at overload concentrations, but the mechanisms leading to initial proliferative events in these cells are unclear. In studies here, cell cycle kinetics, mitogen-activated protein kinase (MAPK) signaling events, and gene expression of activator protein-1 family members were investigated in murine alveolar type II epithelial cells (C10) or rats in vivo after exposure to several coal mine dusts (CMDs) of high or low quartz content. In contrast to results using unexposed C10 cells or cells exposed to the nonpathogenic particle glass beads, flow cytometry showed increased numbers of hypodiploid cells and cells in S phase after addition of DQ12 quartz or CMDs. Using a ribonuclease protection assay, increased mRNA levels of fos and jun family members were seen in response to DQ12 quartz and CMD with high quartz content. Increased phosphorylation of extracellular signal regulated kinases (ERKs)1/2 occurred in DQ12- and CMD-exposed cells by Western blot analysis. The use of the hydroxyl radical scavenger tetramethylthiourea blocked S-phase entry by DQ12 and CMDs as well as the phosphorylation of ERKs. Immunohistochemistry on lung sections of CMD-exposed rats showed chronic activation of phosphorylated ERKs in epithelial cells, supporting the possible role of this signal cascade in proliferation of pulmonary epithelium by PSP in vivo.