Figure 7.

Regulation of fibroblast/myofibroblast accumulation in pulmonary fibrosis. The data presented in this study support a model of fibroblast/myofibroblast accumulation at sites of lung injury depicted in this figure. In this figure, thick solid arrows represent cell movements, whereas thinner dashed arrows represent cell and matrix maturations. Early after lung injury, fibroblasts acquire a migratory/invasive phenotype characterized by the acquisition of cell-autonomous invasive capacity. Concurrent with the development of this intrinsic fibroblast phenotype, potent soluble mediators that markedly augment fibroblast migration (chemoattractants) and invasion (chemoinvasants) are induced in the lungs of patients with IPF and in the bleomycin mouse model of pulmonary fibrosis. After invasion into provisional matrices, fibroblasts lose their initial migratory/invasive phenotype and transition to the matrix-synthetic and contractile phenotype characteristic of myofibroblasts, directed by cytokines, such as TGF-β. Once they have differentiated into myofibroblasts, these cells remain in the provisional matrix, where they secrete increased amounts of collagen and other matrix proteins. Collagen cross-linking and wound contraction then convert the myofibroblast-rich provisional matrices into mature scar/fibrosis.