The Potentially Therapeutic Role of EPAC in Curbing the Process of Idiopathic Pulmonary Fibrosis via Differential Cellular Pathways

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibrosis disease caused by genetic susceptibility (causative) and other indirect risk factors such as smoking, micro-aspiration and air pollution. Repeated damage of lung epithelial cells can cause fibroblast activation and excessive collagen will lead the scar formation and severe fibrosis. It has been decades since drugs for the treatment of IPF were developed, but clinical choices were limited. Exchange Protein directly Activated by cAMP (EPAC), as a newly emerging cAMP (adenosine 3',5'-cyclic monophosphate) downstream molecule, plays a vital role in the cellular pathways of IPF such as inhibiting fibroblast proliferation, stress fiber formation and epithelium cell adhesion, so it may be a novel target for drug development and treatment for curbing IPF. Here, we hypothesize that EPAC may participate in the signaling pathways related to IPF in different cell types (fibroblasts; airway smooth muscle cells; vascular endothelial cells; lung epithelial cells; macrophages; mesenchymal stem cells; T cells), thereby playing a potentially therapeutic role in resisting the process of fibrosis. We summarize the current correlation between EPAC and IPF in these different cell types, and further insights into EPAC will help to optimize the pharmacological treatment for IPF.

Keywords: EPAC; PKA; cAMP; cell types; fibroblasts; idiopathic pulmonary fibrosis.

Figure 1

Domain architecture of EPAC isoforms. We divided them into two functional parts: regulatory region and catalytic region. The individual domains include: CDC25-HD, CDC25 homology domain (catalyzes Rap1 activation16); RA, Ras association domain; REM, Ras exchange motif; cAMP-B, cAMP-binding domains B; DEP, disheveled, EGL-10 and pleckstrin homology domain (localizes EPAC to the plasma membrane upon activation by cAMP17); cAMP-A, cAMP-binding domains A. EPAC2A has the longest sequence while EPAC2C is the shortest, EPAC2B has the resembled functional domain as EPAC1.

Figure 2

Fibroblasts involved in the EPAC pathway and connection with fibrosis. Activation of PKA and EPAC differentially inhibits specific fibroblast functions, activation of EPAC inhibits fibroblast proliferation, and both PKA and EPAC contribute to the inhibition of α-SMA expression and fibroblast transition to myofibroblasts. PGE₂ inhibits lung fibroblast collagen expression and proliferation via independent cAMP effectors. Through FP receptor signals, PGF_2α can enhance collagen synthesis in fibroblasts., Profibrotic effects of angiotensin Ⅱ (Ang Ⅱ) and TGF-β1 can potentially through SMAD inhibition, cAMP activation of EPAC1 and PKA lowers expression of collagens Ⅰ and III. Together, ECM synthesis, fibroblast proliferation and collagen production will aggravate fibrosis.

Figure 3

Pathways and function of EPAC related to fibrosis in different cell types (fibroblast; airway smooth muscle cell; endothelial cell; epithelium cell; macrophage; mesenchymal stem cell; T cell). ↑ means increase or up-regulated; ↓ means decrease or down-regulated.