A New Hope for the Treatment of Idiopathic Pulmonary Fibrosis

by Siphamandla Ngwenya

Idiopathic pulmonary fibrosis (IPF) is progressive and lethal interstitial lung disease that causes scarring (fibrosis) of the lungs, leading to stiffness in the lungs and difficulty in breathing. IPF is rare and sporadic with a mortality rate that has been increasing in recent years and as the term idiopathic suggests the disease is of unknown cause and has no known cure. IPF leads to irreversible lung damage that worsens over time. The two drugs used in the treatment of IPF are pirfenidone and nintedanib, and these drugs have limited efficacy in that they can slow disease progression, but cannot improve or stabilize lung function, and they have tolerability issues. Thus, finding new and effective therapeutic strategies is urgently needed.

Acetylcholine is a neurotransmitter that plays a role in contracting smooth muscle, increasing bodily secretions, and slowing the heart rate. Acetylcholine binds to the muscarinic and/or the nicotinic receptors to stimulate or block body responses. The muscarinic acetylcholine receptor which is the main receptor of acetylcholine has subtypes M1, M2 and M3. The M3 muscarinic receptor has been found to be expressed in fibroblasts and myofibroblasts, and when activated it leads to collagen secretion, and the proliferation of human lung fibroblasts. IPF is characterized by progressive fibrotic remodelling of the lungs and aberrant fibroblast. However, it is not until recently that Liu et. al. (2022) showed that an antagonist of the M3 muscarinic acetylcholine receptor is a potential therapeutic option for the prevention or treatment of IPF.

The M3 muscarinic receptor antagonist in question is darifenacin. Darifenacin is unique among antimuscarinics in that its M3 selectivity could confer advantages in patients who have tachycardia, sleeping disturbances, and impaired cognition while minimizing the risk of safety related adverse reactions as shown in previous studies. Based on these findings, it was concluded that darifenacin is effective and does not have any tolerability issues. The study by Liu et. Al. (2022) aimed to investigate the effects of darifenacin treatment on bleomycin-induced pulmonary fibrosis and to understand the underlying mechanism in a rat model of pulmonary fibrosis.

Enzyme-linked immunosorbent assay (ELISA) was used to measure transforming growth factor β1 (TGF-β1) and tumor necrosis factor-α (TNF-α) expression levels due to the important role they play in the pathogenesis of pulmonary fibrosis. Hydroxyproline detection kit was used to detect hydroxyproline which is induced by bleomycin in lung fibroblasts. To detect expression levels of extracellular signal-regulated kinase (ERK), nuclear factor kappa-B (NF-κB), and microRNA-21 (miR-21) of which are involved in the process of pulmonary fibrosis, western blot, or quantitative real-time PCR (qRT-PCR) was used.

In the study they showed that treatment with darifenacin downregulates the expression levels of hydroxyproline, TGF-β1 and TNF-α level, of which from previous studies have been shown to be elevated in serum samples of pulmonary fibrosis. Previous studies indicated that ERK activation could upregulate NF-κB expression and that the blocking of related signaling pathways of NF-κB could attenuate pulmonary fibrosis. These findings were confirmed in the study, which demonstrated the downregulation of miR-21 and NF-κB when rats were treated with darifenacin.    

As mentioned before, this is the first study to report that muscarinic 3 acetylcholine receptor antagonist may be a potential therapeutic option in the prevention or treatment of pulmonary fibrosis. The study also showed that inhibition the ERK, NF-κB and miR-21 signalling pathway as the major underlying mechanism responsible for the effects of darifenacin. Therefore, the study considers darifenacin to be a potential treatment for IPF. Based on this study, future studies should establish the optimal dosage of darifenacin and should pursue finding other underlying mechanisms that play a role in the attenuation of pulmonary fibrosis.


Liu, Y., Jiang, Y.N., Wang, C., Zhang, H.Y. and Liu, Y. (2022) M3 Muscarinic Acetylcholine Receptor Antagonist Darifenacin Protects against Pulmonary Fibrosis through ERK/NF-κB/ miR-21 Pathway. American Journal of Molecular Biology, 12, 11-22. https://doi.org/10.4236/ajmb.2022.122002.

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