Figure 3

Growth factors and cytokines from macrophages and epithelial cells, along with the inflammatory microenvironment, influence mesenchymal cell survival and phenotype. Particle-stimulated airway epithelial cells and alveolar macrophages produce soluble cytokines and growth factors that stimulate the replication and migration of myofibroblasts. EGFR ligands (HB-EGF and TGF-α) are produced by airway epithelial cells that stimulate epithelial repair and differentiation in an autocrine manner, but also stimulate myofibroblast replication. PDGF-AA and PDGF-BB produced by epithelial cells and macrophages, respectively, drive replication and chemotactic migration of myofibroblasts. IL-1β enhances the activity of PDGF-AA and PDGF-BB by upregulating PDGF receptor-α (PDGFRα) expression. Macrophages are also an abundant source of TNF-α, which stimulates TGF-β1 production by macrophages in an autocrine manner. TGF-β1 stimulates myofibroblast collagen production and growth arrest, which defines a "matrix synthetic phenotype." The myofibroblast phenotype is further defined by a Th1 or Th2 microenvironment. In the presence of Th1 lymphocytes, IFN-γ produced by Th1 cells or IFN-β produced by myofibroblasts stimulates growth arrest and cell death of myofibroblasts and leads to the resolution of a fibrogenic response and tissue repair. In the presence of Th2 lymphocytes, IL-13 produced by Th2 cells activates myofibroblasts to produce PDGF-AA and TGF-β1 in an autocrine manner, which drives myofibroblast survival, replication and matrix production to enhance and sustain a fibrogenic response.