An early phase of proliferation by mesothelial cells and fibroblasts occurs in the lung after asbestos deposition, but the source and identity of the cytokine(s) involved is not clear. In the present study, rats received crocidolite asbestos intratracheally and were killed at 1 and 6 wk later, animals received tritiated thymidine 1 h before death. An increase in inflammatory cells was found in bronchoalveolar and pleural lavage fluids at both times, and after 6 wk the lungs showed fibrosis which was confirmed biochemically. Asbestos fibers were found in alveolar and interstitial macrophages but not in pleural macrophages. In autoradiographs, both mesothelial cells and fibroblasts showed increased DNA synthesis at 1 wk, but only fibroblast labeling was increased at 6 wk. Lavaged macrophages from the lung (alveolar macrophages; AM) and the pleura (pleural macrophages; PLM) were cultured and supernatants tested on rat lung mesothelial cells and fibroblasts in vitro; concentrated lavaged fluids were also tested. At 1 wk, macrophages secreted growth factors for both cell types but the effect was more pronounced using lavage fluids, particularly from the pleura. The increase in fibroblast growth was reduced by an antibody to platelet-derived growth factor, but this had no effect on mesothelial cells. The growth stimulation of these cells was blocked by an antibody to keratinocyte growth factor (KGF). Using cell supernatants and lavage fluids from rats 6 wk after asbestos, growth stimulation was only observed in fibroblasts. The results suggest at least 2 cytokine effects in the lung and pleural space after asbestos exposure; one responsible for fibroblast stimulation is seen up to 6 wk later, while the other, probably involving KGF, stimulates mesothelial cell proliferation in the early response phase after a single exposure to crocidolite.