Prostaglandin E2 and the pathogenesis of pulmonary fibrosis

Abstract

Prostaglandin (PG)E(2) is a bioactive eicosanoid that regulates many biologically important processes in part due to its ability to signal through four distinct G-protein-coupled receptors with differential signaling activity and unique expression patterns in different cell types. Although PGE(2) has been linked to malignancy in many organs, it is believed to play a beneficial role in the setting of fibrotic lung disease. This is in part due to the ability of PGE(2) to limit many of the pathobiologic features of lung fibroblasts and myofibroblasts, including the ability of PGE(2) to limit fibroblast proliferation, migration, collagen secretion, and, as originally reported in the Journal by us in 2003, the ability to limit transforming growth factor (TGF)-β-induced myofibroblast differentiation. In the setting of lung fibrosis, PGE(2) production and signaling is often diminished. In the last 8 years, significant advances have been made to better understand the dysregulation of PGE(2) production and signaling in the setting of lung fibrosis. We also have a clearer picture of how PGE(2) inhibits myofibroblast differentiation and the receptor signaling pathways that can influence fibroblast proliferation. This review highlights these recent advances and offers new insights into the potential ways that PGE(2) and its downstream signals can be regulated for therapeutic benefit in a disease that has no validated treatment options.

Figure 1.

The homeostatic signaling of prostaglandin (PG)E₂ in alveolar epithelial cells (AECs) and fibroblasts. Diagram showing that in the normal lung fibroblast, PGE₂ functions to limit proliferation, collagen secretion, and myofibroblast differentiation. With respect to apoptosis, PGE₂ can induce apoptosis in fibroblasts while protecting lung AECs.

Figure 2.

Transforming growth factor (TGF)-β1 induces the formation of focal adhesions, but cotreatment with PGE₂ prevents focal adhesion formation. IMR90 lung fibroblast cells were serum starved before treatment with serum-free media alone (control) or TGF-β1 alone (2 ng/ml) or in combination with 10 nM PGE₂ for 24 hours. Cells were fixed and stained with FITC-phalloidin (green) to visualize F-actin, Cy3–anti-paxillin (red), and DAPI (blue) for the nuclei and analyzed by laser-scanning confocal microscopy. Areas of coimmunofluorescence with FITC and paxillin are focal adhesions (orange/yellow). The colocalization of F-actin and paxillin was confirmed by Z-stack analysis.

Figure 3.

Alternations in PGE₂ production and signaling that have been noted in fibrotic fibroblasts. Schematic showing the epigenetic and inflammatory signals that contribute to the dysregulation of PGE₂ production and signaling in the fibrotic lung. Green boxes represent changes due to epigenetic alterations. Yellow boxes denote changes due to inflammatory signals.