PGD₂ modulates fibroblast-mediated native collagen gel contraction

Repair of tissues is a necessary step in restoring tissue function following injury consequent to inflammation. Many inflammatory mediators are capable of modulating not only the activity of "inflammatory cells" but also of modulating functions of parenchymal cells that may contribute to repair. Disordered repair is believed to contribute to tissue dysfunction in many inflammatory diseases, including bronchial asthma. The current study evaluated the ability of prostaglandin D₂ (PGD₂) to modulate fibroblast repair using the in vitro contraction of three-dimensional native collagen gels as a model system. PGD₂ stimulated gel contraction in a concentration- and time-dependent manner. In contrast, the PGD₂ analog BW245C inhibited contraction. Both effects were blocked by a DP-receptor blocker (AH6809). Neither TP receptor blocker SQ29548 nor protein kinase (PK) A antagonist KT5720 hand an effect on PGD₂-stimulated contraction, suggesting action through a novel prostaglandin D receptor. PKC inhibitor calphostin-C (10^-6 M) blocked the PGD₂ stimulation of gel contraction. A calcium-independent PKC-ε inhibitor (Ro31-8220), but not calcium-dependent PKC-α and -β inhibitors, also blocked the PGD₂ effect on contraction, implying a role for a calcium-independent pathway. This study, therefore, supports a role for PGD₂ in tissue repair and remodeling. These effects of PGD₂ appear to be mediated through receptor-signal transduction pathways different from the cAMP-PKA pathways mediating the proinflammatory activity of PGD₂, creating the possibility for selective therapeutic manipulation.