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1 Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA
* To whom correspondence should be addressed. E-mail: panchenko{at}biochem.bumc.bu.edu.
Elastase degradation of elastin within alveolar walls is an important event in the development of pulmonary emphysema. In addition to elastolytic activities, elastases release growth factors from extracellular matrices and interstitial cell surfaces that can regulate elastogenesis and other cellular responses. In the present study, we demonstrate that brief treatment of matrix-laden rat pulmonary fibroblast cultures with pancreatic elastase results in the release of soluble heparin-binding epidermal growth factor-like growth factor (HB-EGF) concomitant with a decrease in HB-EGF binding to both heparan sulfate proteoglycan (HSPG) and receptor sites on the cells. In undigested, matrix-laden fibroblasts, HB-EGF significantly down-regulates elastin mRNA via activation of epidermal growth factor receptor (EGF-R). Results from nuclear run-on analyses show that HB-EGF down-regulates elastin mRNA via transcriptional suppression. HB-EGF treatment stimulates MEK-dependent ERK1/2 phosphorylation and leads to nuclear accumulation of Fra-1. Blocking ERK1/2 activation by MEK1/2 inhibitors (PD98059 or U0126) diminishes HB-EGF-induced Fra-1 accumulation and subsequent down-regulation of elastin mRNA. Co-addition of two elastase-released growth factors, HB-EGF and FGF-2, results in an additive inhibitory effect on elastin mRNA levels. Further, HB-EGF addition to pulmonary fibroblasts increases FGF-2 mRNA and protein levels. These data suggest that HB-EGF and FGF-2 act in concert to regulate the synthesis of elastin in injury/repair situations.
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