The Roles of Various Prostaglandins in Fibrosis: A Review

Abstract

Organ fibrosis is a common pathological result of various chronic diseases with multiple causes. Fibrosis is characterized by the excessive deposition of extracellular matrix and eventually leads to the destruction of the tissue structure and impaired organ function. Prostaglandins are produced by arachidonic acid through cyclooxygenases and various prostaglandin-specific synthases. Prostaglandins bind to homologous receptors on adjacent tissue cells in an autocrine or paracrine manner and participate in the regulation of a series of physiological or pathological processes, including fibrosis. This review summarizes the properties, synthesis, and degradation of various prostaglandins, as well as the roles of these prostaglandins and their receptors in fibrosis in multiple models to reveal the clinical significance of prostaglandins and their receptors in the treatment of fibrosis.

Keywords: PGD2; PGE2; PGF2α; PGI2; TXA2; fibrosis; myofibroblast.

Figure 1

PG production. Membrane phospholipids are metabolized into AA by the PLA2, PLD, or PLC pathways. AA is then converted to PGs and IL by the COX and LOX pathways, respectively. The generated PGH2 is transformed to PGE2, PGD2, PGI2, PGF2α, and thromboxane A2 (TXA2) by individual enzymes, all of which function by binding to target receptors on their own cells or adjacent cells in an autocrine or paracrine manner.

Figure 2

The antifibrotic effects of PGD2, PGE2, and PGI2. PGD2, PGE2, and PGI2 activate cAMP by binding to corresponding receptors, and then inhibit the proliferation, transformation, and ECM generation of fibroblasts, and promote cell apoptosis by affecting downstream signals. At the same time, PGD2 also acts on the CRTH2 receptor on γδT cell, promoting its release of anti-fibrosis IL-10 to inhibit fibrosis. PGE2 can act on EP2/4 receptors in epithelial cells and Tubular Cells in an autocrine way, thereby inhibiting the apoptosis of these functional cells.

Figure 3

The pto-fibrotic effects of PGF2α and TXA2. PGF2α acts on the FP receptor on the surface of fibroblasts to induce cell proliferation and collagen expression by activating PKC/Rho kinase—ROCK (Rho-associated kinase) pathway. TXA2 secreted by platelets acts on TP receptors and promotes fibrosis by activating cAMP signaling.