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FGF-1 Activates several Signaling Pathways as an Antifibrogenic Mediator in Human Lung Fibroblasts

Background: In idiopathic pulmonary fibrosis (IPF), fibroblasts characteristically perform abnormal turnover of the extracellular matrix by downregulating matrix metalloproteinase-1 (MMP-1) and upregulating collagen I and alpha-smooth muscle actin (α-SMA), mostly through the stimulation of transforming growth factor beta-1 (TGF-β1). Alternatively, fibroblast growth factor-1 combined with heparin (FGF-1/H) inhibits these effects. In view of this, the aim of this research was to determine which signaling pathways stimulated by FGF1/H in fibroblasts upregulate MMP-1 and downregulate collagen I and TGF-β1-induced α-SMA expression in human lung fibroblasts (HLF).

Methods: Cells were stimulated with FGF-1/H in the presence or absence of selective pharmacological inhibitors of different signaling pathways to block MMP-1, collagen I, and TGF-β1-induced α-SMA expression. Expression levels of the aforementioned proteins and genes were evaluated by RT-qPCR and Western blot.

Results: Data showed that FGF-1/H upregulates MMP-1 chiefly through the JNK, MEK, and TGF-β/Smad signaling pathways; meanwhile, it downregulates collagen I expression mostly through the MEK, p38, and PI3K signaling pathways; and downregulation of TGF-β1-induced α-SMA expression happens predominantly through the JNK, MEK, and TGF-β/Smad signaling pathways. On the other hand, pharmacological inhibitors alone had no effect on the expression of MMP-1 or collagen I. Likewise, FGF-1/H activates ERK1, AKT1, JNK1, and p38 proteins and upregulates transcription factor ETS-1. These findings might provide useful insights for future pharmacological treatments targeting fibrosing lung diseases such as IPF.

Conclusion: FGF-1/H stimulates different signaling pathways to upregulate MMP- 1, downregulate collagen I and to inhibit TGF-β1-induced α-SMA expression.


Carlos Ramos, Carina Becerril, Víctor Ruiz, Georgina González Ávila, MC Negrete-García, Bettina Sommer, Ana Esquivel, Julia Pérez-Ramos and Martha Montaño

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