Regulation of lung elastin gene expression and fibroblast migration by elastase-released growth factors
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Degradation of elastin within alveolar walls is an important event in the development of pulmonary emphysema. Elastases release growth factors from extracellular matrices and interstitial cell surfaces, which can regulate the repair process. Brief treatment of matrix-laden rat pulmonary fibroblast cultures with porcine pancreatic elastase results in the release of soluble heparin-binding epidermal growth factor-like growth factor (HB-EGF) together with previously identified fibroblast growth factor-2 (FGF-2). In matrix-laden pulmonary fibroblasts, HB-EGF and two other EGF family ligands, i.e. EGF and transforming growth factor a, significantly down-regulate elastin mRNA via activation of the EGF receptor. HB-EGF treatment initiates a signaling pathway involving extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation and subsequent nuclear accumulation of Fra-1, which leads to inhibition of elastin gene transcription. Co-addition of HB-EGF and FGF-2 results in an additive inhibitory effect on elastin mRNA levels. The increased effect of HB-EGF and FGF-2 on elastin mRNA is associated with their additive actions on ERK1/2 activation, c-fos mRNA induction and Fra-1 nuclear accumulation. Further, HB-EGF induces FGF-2 mRNA and protein, suggesting a potential role of endogenous FGF-2 in mediating HB-EGF-dependent responses. Cell migration represents an important component of injury/repair. A chemotactic activity for pulmonary fibroblasts was identified within the elastase-released products. Characterization of this activity indicates that elastase-released FGF-2 is a major chemotactic component of the elastase digest. Furthermore, our data strongly suggest that the elastase digest contains another component(s) that potentiates the chemotactic activity of FGF-2. Collectively, the present study supports a model in which elastase-released growth factors and other components act in concert to regulate elastin gene expression and cell migration in injury/repair situations.
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