Perspectives of PDE inhibitor on treating idiopathic pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) without an identifiable cause. If not treated after diagnosis, the average life expectancy is 3-5 years. Currently approved drugs for the treatment of IPF are Pirfenidone and Nintedanib, as antifibrotic drugs, which can reduce the decline rate of forced vital capacity (FVC) and reduce the risk of acute exacerbation of IPF. However these drugs can not relieve the symptoms associated with IPF, nor improve the overall survival rate of IPF patients. We need to develop new, safe and effective drugs to treat pulmonary fibrosis. Previous studies have shown that cyclic nucleotides participate in the pathway and play an essential role in the process of pulmonary fibrosis. Phosphodiesterase (PDEs) is involved in cyclic nucleotide metabolism, so PDE inhibitors are candidates for pulmonary fibrosis. This paper reviews the research progress of PDE inhibitors related to pulmonary fibrosis, so as to provide ideas for the development of anti-pulmonary fibrosis drugs.

Keywords: PDE inhibitor; anti-fibrosis; cAMP; cGMP; pulmonary fibrosis; senescence.

FIGURE 1

Domain architecture of EPAC isoforms: EPAC proteins are single polypeptide molecules which consist of an N-terminal regulatory region and a C-terminal catalytic region. The catalytic region at the C terminus is mainly composed of three structural and: Ras exchange motif (REM), Ras association (RA), CDC25 homology domain [also known as the guanine nucleotide exchange factor for Ras-like small GTPases (RasGEF) domain] responsible for nucleotide exchange activity. The two subtypes had different structures in the N-terminal regulatory region. The Epac2A regulation region contains two CAMP-binding domains, CNB-B and CNB-A. However, Epac1, Epac2A and Epac2B all have Disheveled/Egl-10/pleckstrin (DEP) domains, which are correlated with subcellular localization of Epac. Epac1 is widely expressed in human tissues, such as the hippocampus, thyroid, breast, and lung. EPAC2A is mainly expressed in the central nervous system, pituitary gland and adrenal gland.

FIGURE 2

Epac via differential cellular pathways inhibit the process of IPF. ↑ means increase or upregulated; ↓ means decrease or downregulated.

FIGURE 3

PKA pathways inhibit the process of IPF. cAMP/PKA can inhibit endoplasmic reticulum stress and promote dedifferentiation of myofibroblasts to realize anti-fibrosis. p75^NTR regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. But it needs to be further verified in pulmonary fibrosis.

FIGURE 4

NO/sGC-cGMP pathway in pulmonary fibrosis. Aging leads to a decrease in the antioxidant capacity of Nrf2. This pro-oxidant shift results in NOS decoupling and a concurrent decrease in NO signaling and PKG activity.