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ARTICLE
EDITORIAL FOCUS
Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät, Institut für 1Neurobiochemie and 3Immunologie, 4Klinik für Kardiologie, Angiologie und Pneumologie; Magdeburg, Germany; and 2Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia
Submitted 15 September 2004 ; accepted in final form 19 November 2004
Among the four protease-activated receptors (PARs), PAR-1 plays an important role in normal lung functioning and in the development of lung diseases, including fibrosis. 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 expression levels of PAR-1 and PAR-3, whereas a fourfold higher expression level of PAR-2 was observed in fibrotic cells compared with 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 Ca2+ level. PAR-1 activation by thrombin or receptor-activating peptide downregulated expression of all three PARs in lung fibroblasts, with maximal effect at 3–6 h, whereas expression returned toward basal level after 24 h. Furthermore, PAR-1 agonists dose dependently increased PGE2 secretion from lung fibroblasts and induction of cyclooxygenase-2 expression. We then found that PGE2 downregulated 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.
thrombin; cyclooxygenase; cyclic adenosine 5'-monophosphate; prostanoid
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