Perspectives of PDE Inhibitor on Treating Idiopathic Pulmonary Fibrosis

Overview

Journal Front Pharmacol

Date 2023 Mar 3

PMID 36865908

Authors

Xudan Yang

Zhihao Xu

Songhua Hu

Juan Shen

Affiliations

Soon will be listed here.

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.

Citing Articles

Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding....

Wang Q, Liu X, Yuan H, Zhang F, Wu J, Yang D ACS Pharmacol Transl Sci. 2025; 8(1):256-269.

PMID: 39816787 PMC: 11729434. DOI: 10.1021/acsptsci.4c00671.

Investigation of the protective effect of cilostazol on acute lung injury-mediated inflammation and in silico molecular modelling studies of inflammatory signalling pathway: a repurposing study.

Misar P, Otari K Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 39754679 DOI: 10.1007/s00210-024-03734-z.

Nerandomilast Improves Bleomycin-Induced Systemic Sclerosis-Associated Interstitial Lung Disease in Mice by Regulating the TGF-β1 Pathway.

Liu Y, Liu Z, Li X, Li W, Yang Z, Jiao R Inflammation. 2024; .

PMID: 39438343 DOI: 10.1007/s10753-024-02153-9.

Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease.

Nishioka Y, Araya J, Tanaka Y, Kumanogoh A Inflamm Regen. 2024; 44(1):34.

PMID: 39026335 PMC: 11264521. DOI: 10.1186/s41232-024-00345-2.

circGRHPR inhibits aberrant epithelial-mesenchymal transformation progression of lung epithelial cells associated with idiopathic pulmonary fibrosis.

Wu W, Wang Z, Zhang H, Zhang X, Tian H Cell Biol Toxicol. 2024; 40(1):7.

PMID: 38267743 PMC: 10808371. DOI: 10.1007/s10565-024-09839-8.

References

Hong Q, Zhang Y, Lin W, Wang W, Yuan Y, Lin J . Negative Feedback of the cAMP/PKA Pathway Regulates the Effects of Endoplasmic Reticulum Stress-Induced NLRP3 Inflammasome Activation on Type II Alveolar Epithelial Cell Pyroptosis as a Novel Mechanism of BLM-Induced Pulmonary Fibrosis. J Immunol Res. 2022; 2022:2291877. PMC: 9410862. DOI: 10.1155/2022/2291877. View

Sachs B, Baillie G, McCall J, Passino M, Schachtrup C, Wallace D . p75 neurotrophin receptor regulates tissue fibrosis through inhibition of plasminogen activation via a PDE4/cAMP/PKA pathway. J Cell Biol. 2007; 177(6):1119-32. PMC: 2064370. DOI: 10.1083/jcb.200701040. View

Roscioni S, Maarsingh H, Elzinga C, Schuur J, Menzen M, Halayko A . Epac as a novel effector of airway smooth muscle relaxation. J Cell Mol Med. 2010; 15(7):1551-63. PMC: 3823199. DOI: 10.1111/j.1582-4934.2010.01150.x. View

Gurney M, DAmato E, Burgin A . Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer's disease. Neurotherapeutics. 2014; 12(1):49-56. PMC: 4322084. DOI: 10.1007/s13311-014-0309-7. View

Hatzelmann A, Morcillo E, Lungarella G, Adnot S, Sanjar S, Beume R . The preclinical pharmacology of roflumilast--a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulm Pharmacol Ther. 2010; 23(4):235-56. DOI: 10.1016/j.pupt.2010.03.011. View

Schinner E, Wetzl V, Schlossmann J . Cyclic nucleotide signalling in kidney fibrosis. Int J Mol Sci. 2015; 16(2):2320-51. PMC: 4346839. DOI: 10.3390/ijms16022320. View

Abdel-Magid A . PDE10 Inhibitors as Potential Treatment for Schizophrenia. ACS Med Chem Lett. 2014; 4(2):161-2. PMC: 4027377. DOI: 10.1021/ml4000194. View

Abdel-Magid A . Potential Treatment of Cognitive Impairment in Schizophrenia by Phosphodiesterase 2 (PDE2) Inhibitors. ACS Med Chem Lett. 2017; 8(1):17-18. PMC: 5238480. DOI: 10.1021/acsmedchemlett.6b00514. View

Wen W, Lee S, Siang R, Koh R . Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview. Adv Ther. 2017; 34(6):1245-1269. DOI: 10.1007/s12325-017-0547-2. View

10.

Movsesian M . PDE3 inhibition in dilated cardiomyopathy: reasons to reconsider. J Card Fail. 2004; 9(6):475-80. DOI: 10.1016/s1071-9164(03)00135-0. View

11.

Zieba B, Artamonov M, Jin L, Momotani K, Ho R, Franke A . The cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac, induces smooth muscle relaxation by down-regulation of RhoA activity. J Biol Chem. 2011; 286(19):16681-92. PMC: 3089510. DOI: 10.1074/jbc.M110.205062. View

12.

Gopalakrishna K, Boyd K, Artemyev N . Mechanisms of mutant PDE6 proteins underlying retinal diseases. Cell Signal. 2017; 37:74-80. PMC: 5554458. DOI: 10.1016/j.cellsig.2017.06.002. View

13.

Torphy T . Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998; 157(2):351-70. DOI: 10.1164/ajrccm.157.2.9708012. View

14.

Michie A, LOBBAN M, Muller T, Harnett M, Houslay M . Rapid regulation of PDE-2 and PDE-4 cyclic AMP phosphodiesterase activity following ligation of the T cell antigen receptor on thymocytes: analysis using the selective inhibitors erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA) and rolipram. Cell Signal. 1996; 8(2):97-110. DOI: 10.1016/0898-6568(95)02032-2. View

15.

Otoupalova E, Smith S, Cheng G, Thannickal V . Oxidative Stress in Pulmonary Fibrosis. Compr Physiol. 2020; 10(2):509-547. DOI: 10.1002/cphy.c190017. View

16.

Bender A, Beavo J . Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006; 58(3):488-520. DOI: 10.1124/pr.58.3.5. View

17.

Bollen E, Prickaerts J . Phosphodiesterases in neurodegenerative disorders. IUBMB Life. 2012; 64(12):965-70. DOI: 10.1002/iub.1104. View

18.

Rabal O, Sanchez-Arias J, Cuadrado-Tejedor M, de Miguel I, Perez-Gonzalez M, Garcia-Barroso C . Multitarget Approach for the Treatment of Alzheimer's Disease: Inhibition of Phosphodiesterase 9 (PDE9) and Histone Deacetylases (HDACs) Covering Diverse Selectivity Profiles. ACS Chem Neurosci. 2019; 10(9):4076-4101. DOI: 10.1021/acschemneuro.9b00303. View

19.

Li H, Zhang Y, Liu M, Fan C, Feng C, Lu Q . Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis. Acta Pharm Sin B. 2022; 12(1):228-245. PMC: 8799862. DOI: 10.1016/j.apsb.2021.04.007. View

20.

King Jr T, Bradford W, Castro-Bernardini S, Fagan E, Glaspole I, Glassberg M . A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014; 370(22):2083-92. DOI: 10.1056/NEJMoa1402582. View