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From the Department of Pathology,* Division of Molecular and Cellular Pathology, and The Cell Adhesion and Matrix Research Center; and the Departments of Pediatrics and Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama
Distinct subpopulations of fibroblasts contribute to lung fibrosis, although the mechanisms underlying fibrogenesis in these subpopulations are not clear. Differential expression of the glycophosphatidylinositol-linked protein Thy-1 affects proliferation and myofibroblast differentiation. Lung fibroblast populations selected on the basis of Thy-1 expression by cell sorting were examined for responses to fibrogenic stimuli. Thy-1 (–) and Thy-1 (+) fibroblast populations were treated with platelet-derived growth factor-BB, interleukin-1ß, interleukin-4, or bleomycin and assessed for activation of transforming growth factor (TGF)-ß, Smad3 phosphorylation, and 
-smooth muscle actin and fibronectin expression. Thy-1 (–) fibroblasts responded to these stimuli with increased TGF-ß activity, Smad3 phosphorylation, and expression of -smooth muscle actin and fibronectin, whereas Thy-1 (+) fibroblasts resisted stimulation. The unresponsiveness of Thy-1 (+) cells is not because of defective TGF-ß signaling because both subsets respond to exogenous active TGF-ß. Rather, Thy-1 (–) fibroblasts activate latent TGF-ß in response to fibrogenic stimuli, whereas Thy-1 (+) cells fail to do so. Defective activation is common to multiple mechanisms of TGF-ß activation, including thrombospondin 1, matrix metalloproteinase, or plasmin. Thy-1 (–) lung fibroblasts transfected with Thy-1 also become resistant to fibrogenic stimulation, indicating that Thy-1 is a critical biological response modifier that protects against fibrotic progression by controlling TGF-ß activation. These studies provide a molecular basis for understanding the differential roles of fibroblast subpopulations in fibrotic lung disease through control of latent TGF-ß activation.
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