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1 Institut fuer Neurobiochemie, Otto-von-Guericke-Universitaet Magdeburg, Magdeburg, Germany
2 Institut fuer Neurobiochemie, Otto-von-Guericke-Universitaet Magdeburg, Magdeburg, Germany; Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russian Federation
3 Institut fuer Immunologie, Otto-von-Guericke-Universitaet Magdeburg, Magdeburg, Germany
4 Klinik fuer Kardiologie, Angiologie und Pneumologie, Otto-von-Guericke-Universitaet Magdeburg, Magdeburg, Germany
* To whom correspondence should be addressed. E-mail: georg.reiser{at}medizin.uni-magdeburg.de.
Among the four protease-activated receptors (PARs), especially PAR-1 plays an important role in normal lung functioning and in the development of lung diseases, including fibrosis. Here we compared the expression and functional activity of PARs in normal and fibrotic human lung fibroblasts. Both normal and fibrotic cells express PAR-1, -2, and -3 with PAR-2 showing the lowest level. There was no significant difference between normal and fibrotic fibroblasts in the expression levels of PAR-1 and PAR-3, while a 4-fold higher expression level of PAR-2 was observed in fibrotic cells as compared to normal cells. Ca2+ imaging studies revealed apparently only PAR-1-induced Ca2+ signaling in lung fibroblasts. PAR-1 agonists, thrombin and synthetic activating peptide, induced concentration-dependent Ca2+ mobilization with EC50 values of 5 nM and 1 µM, respectively. The neutrophil protease cathepsin G produced a transient Ca2+ response followed by disabling PAR-1, whereas elastase did not affect the Ca2+ level. PAR-1 activation by thrombin or receptor-activating peptide down-regulated expression of all three PARs in lung fibroblasts with maximal effect at 3 to 6 h, while the expression returned towards basal level after 24 h. Furthermore, PAR-1 agonists dose-dependently increased prostaglandin E2 (PGE2) secretion from lung fibroblasts and induction of cyclooxygenase-2 expression. Then we found that PGE2 down-regulated the expression of all three PARs. The effect of PGE2 was continuously growing with time. Furthermore, PGE2 exerts its effect through the EP2 receptor that was confirmed using the selective EP2 agonist butaprost. This novel autocrine feedback mechanism of PGE2 in lung fibroblasts seems to be an important regulator in lung physiology and pathology.
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