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Protease-activated receptor-1 in human lung fibroblasts mediates a negative feedback downregulation via prostaglandin E₂

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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