Abstract
BackgroundAn altered susceptibility of lung fibroblasts to Fas-induced apoptosis has been implicated in the pathogenesis of pulmonary fibrosis; however, the underlying mechanism is not completely understood. Here, we studied the susceptibility of lung fibroblasts, obtained from patients with (f-fibs) and without pulmonary fibrosis (n-fibs), to FasL- (CD95L/APO-1) induced apoptosis in relation to the expression and the amounts of membrane-bound and soluble Fas. We also analysed the effects of tumor necrosis factor-β on FasL-induced cell death.MethodsApoptosis was induced with recombinant human FasL, with and without prior stimulation of the fibroblasts with tumor necrosis factor-α and measured by a histone fragmentation assay and flow cytometry. The expression of Fas mRNA was determined by quantitative PCR. The expression of cell surface Fas was determined by flow cytometry, and that of soluble Fas (sFas) was determined by enzyme-linked immunosorbent assay.ResultsWhen compared to n-fibs, f-fibs were resistant to FasL-induced apoptosis, despite significantly higher levels of Fas mRNA. F-fibs showed lower expression of surface-bound Fas but higher levels of sFas. While TNF-α increased the susceptibility to FasL-induced apoptosis in n-fibs, it had no pro-apoptotic effect in f-fibs.ConclusionsThe data suggest that lower expression of surface Fas, but higher levels of apoptosis-inhibiting sFas, contribute to the resistance of fibroblasts in lung fibrosis against apoptosis, to increased cellularity and also to increased formation and deposition of extracellular matrix.
Highlights
An altered susceptibility of lung fibroblasts to Fas-induced apoptosis has been implicated in the pathogenesis of pulmonary fibrosis; the underlying mechanism is not completely understood
We found no significant differences in the phenotypic characteristics of fibroblasts which were derived from different patient groups
The matrix production of fibroblasts isolated from fibrotic and non-fibrotic lung tissues was analyzed: F-fibs produced significantly more extracellular matrix (ECM) proteins, including collagen, than n-fibs (Fig. 1B) independent from the underlying disease
Summary
An altered susceptibility of lung fibroblasts to Fas-induced apoptosis has been implicated in the pathogenesis of pulmonary fibrosis; the underlying mechanism is not completely understood. We studied the susceptibility of lung fibroblasts, obtained from patients with (f-fibs) and without pulmonary fibrosis (n-fibs), to FasL- (CD95L/APO-1) induced apoptosis in relation to the expression and the amounts of membrane-bound and soluble Fas. We analysed the effects of tumor necrosis factor-β on FasL-induced cell death. Lung fibrosis is the final common and often irreversible pathway of different lung diseases, such as idiopathic interstitial pneumonitis (idiopathic pulmonary fibrosis) and granulomatous diseases (sarcoidosis) [1,2,3] Though these diseases are different in their etiology, all are characterized by zones of lung injury where varying numbers of fibroblasts proliferate and contribute to the accumulation of extracellular matrix (ECM). TRAIL induces programmed cell death in many tumor cells, but not in normal, non-neoplastic cells [5]
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