Figure 4.

STAT transcription factor signaling outcomes in mesenchymal cells that contribute to pulmonary fibrogenesis. Multiple signals, either endogenous factors (cytokines and growth factors) or environmental factors (metals, particles, nanoparticles), activate STAT signaling that leads to outcomes involved in fibrogenesis and tissue repair. IL-13 is increased by allergens or certain metals and particles to activate STAT-6, which in turn results in Th2 inflammatory responses that include the production of profibrogenic growth factors, PDGF-AA and TGF-β1. These growth factors are also increased by metals, particles and nanoparticles. PDGF-AA and HB-EGF stimulate STAT-3 to turn on a mesenchymal cell "survival program." Metals and particles also increase the production of reactive oxygen species (ROS) through NADPH oxidase activity or increase the production of interferons (IFNs). ROS or IFNs stimulate STAT-1 to promote growth arrest and apoptosis of mesenchymal cells. Therefore, the proapoptotic action of STAT-1 opposes the prosurvival and antiapoptotic actions of STAT-3 and STAT-6 for mesenchymal cells.