In human lung fibroblasts, PAR-1 activation induces PGE2 secretion, which subsequently downregulates the expression of PAR-1, -2, and -3 through the EP2 receptor.
PAR-1 activation in human lung fibroblasts induces a novel autocrine negative feedback loop via PGE2 and the EP2 receptor that downregulates PAR expression.
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. Ca(2+) imaging studies revealed apparently only PAR-1-induced Ca(2+) signaling in lung fibroblasts. PAR-1 agonists, thrombin and synthetic activating peptide, induced concentration-dependent Ca(2+) mobilization with EC(50) values of 5 nM and 1 microM, respectively. The neutrophil protease cathepsin G produced a transient Ca(2+) response followed by disabling PAR-1, whereas elastase did not affect Ca(2+) 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 PGE(2) secretion from lung fibroblasts and induction of cyclooxygenase-2 expression. We then found that PGE(2) downregulated expression of all three PARs. The effect of PGE(2) was continuously growing with time. Furthermore, PGE(2) exerts its effect through the EP2 receptor that was confirmed using the selective EP2 agonist butaprost. This novel autocrine feedback mechanism of PGE(2) in lung fibroblasts seems to be an important regulator in lung physiology and pathology.
Sokolova et al. (Thu,) conducted a other in Lung fibrosis. PAR-1 agonists (thrombin and synthetic activating peptide) vs. Basal level / Normal fibroblasts was evaluated on Expression and functional activity of PARs and Ca(2+) signaling. In human lung fibroblasts, PAR-1 activation induces PGE2 secretion, which subsequently downregulates the expression of PAR-1, -2, and -3 through the EP2 receptor.
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