Prostaglandin D2 Inhibits Collagen Secretion From Lung Fibroblasts by Activating the DP Receptor

Abstract

Abstract. Lung fibroblasts are responsible for collagen secretion during normal tissue repair and the development of fibrosis. Many other prostaglandins have been reported to regulate collagen synthesis in lung fibroblasts, but the role of prostaglandin D 2 (PGD 2 ) is unknown. In this study, we investigated the effect of PGD 2 on type I collagen secretion in human lung fibroblasts. Pretreatment with PGD 2 (0.1 -10 μM, 1 h) significantly attenuated type I collagen secretion to the cell supernatant induced by transforming growth factor-β (TGF-β). Although an agonist on chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) did not have any effect, the prostanoid DP-receptor agonist BW245C (0.01 -1 μM) suppressed TGF-β-induced collagen secretion. PGD 2 and BW245C significantly increased intracellular cAMP level. One-hour pretreatment with forskolin (0.1 -10 μM), dibutyryl-cAMP (0.01 -1 mM), and the protein kinase A (PKA)-activator N 6 -phenyl-cyclic AMP (100 μM) significantly reduced TGF-β-induced collagen secretion, while exchange protein activated by cAMP (Epac) activator 8-bromo-2′-Omethyladenosine-3′,5′-cyclic AMP (10 μM) did not affect collagen deposition. These results suggest that PGD 2 inhibits TGF-β-induced collagen secretion via intracellular cAMP accumulation through activating DP receptor.

Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A

“…studies have demonstrated that human lung fibroblasts are highly responsive to prostaglandin E 2 (PGE 2 ), prostaglandin D 2 (PGD 2 ), and prostacyclin (PGI 2 ) in terms of cAMP activation and inhibition of myofibroblast activation (13,34,38). We also showed that PKA can be rapidly activated by endothelin-1 or by ATP through cyclooxygenase (COX)-mediated prostanoid synthesis in vascular smooth muscle cells (30,35,37).…”

Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis

“…Our group previously showed that PGD 2 attenuates collagen secretion induced by TGF-β in human lung fibroblasts by activating D-prostanoid (DP) receptor [31]. Another group demonstrated that PGD 2 inhibits proliferation of mouse lung fibroblasts via DP receptor [32].…”

Eicosanoids in tissue repair

“…In an experimental model of skin wound healing, PGD 2 and its degradation products were proposed to reduce inflammation via the activation of PPARγ, thus contributing to resolution after the inflammatory phase of tissue repair. In addition to the potential proresolving effects of PGD 2 metabolites, PGD 2 itself was reported to suppress collagen production and the recruitment of pulmonary fibroblasts by engaging its high affinity receptor DP1 . This suggests that despite its proinflammatory roles in type 2 immune responses, PGD 2 can act as a negative regulator of airway remodeling.…”