PDE4 inhibitor DC591017 ameliorates pulmonary fibrosis through modulating fibroblasts-epithelial cells-alternatively
Shuyue Lei1, Jian Li2, Tao Yang1
1State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Purpose:
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause, characterized by irreversible lung fibrosis, declining respiratory function, and high mortality. Phosphodiesterase 4 (PDE4) regulates physiological responses in immune and parenchymal cells by hydrolyzing cyclic adenosine monophosphate (cAMP), and its inhibition is regarded as an effective therapeutic strategy for pulmonary diseases. The PDE4 inhibitor DC591017 has demonstrated potent anti-inflammatory activity. However, its therapeutic efficacy and the underlying mechanisms in IPF remain unclear.
Methods:
The bleomycin (BLM)-induced mouse model of pulmonary fibrosis was employed to evaluate the in vivo pharmacodynamics of orally administered DC591017. Furthermore, in vitro studies elucidated the cellular mechanisms of DC591017, highlighting its role in modulating lung fibroblasts, epithelial cells, and macrophages. Lung-on-a-chip models to further evaluate the regulatory effect of DC591017 on the macrophages-fibroblasts-epithelial cells microenvironment.
Results:
Oral administration of DC591017 (10 mg/kg) significantly mitigated weight loss, improved histopathological lung damage, and reduced collagen deposition, accompanied by lung function improvement, showing comparable efficacy to nintedanib. Mechanistic studies revealed that DC591017 exerted anti-fibrotic effects by directly inhibiting fibroblasts activation and migration, and suppressing epithelial-mesenchymal transition (EMT). Besides its classical pharmacological action on macrophage function, DC591017 also inhibited Alternatively activated (M2) macrophages polarization and decreased dendritic cell infiltration. Lung-on-a-chip models further demonstrated that DC591017 alleviated fibrosis by modulating macrophages-fibroblasts-epithelial cells interactions.
Conclusion:
As a novel PDE4 inhibitor, DC591017 exhibited potent anti-fibrotic activity by modulating the interaction of multiple pathological cells, thus ensuring its potential as a promising therapeutic candidate for IPF.
Insights
The novel phosphodiesterase 4 (PDE4) inhibitor DC591017 shows promise for treating idiopathic pulmonary fibrosis (IPF). This drug effectively reduced lung fibrosis and improved lung function in a mouse model by modulating key cellular interactions.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Immunology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with high mortality.
- Phosphodiesterase 4 (PDE4) inhibition is a potential therapeutic strategy for pulmonary diseases.
- The efficacy and mechanisms of the PDE4 inhibitor DC591017 in IPF are not well understood.
Purpose of the Study:
- To evaluate the therapeutic efficacy of DC591017 in a bleomycin-induced pulmonary fibrosis mouse model.
- To elucidate the cellular mechanisms underlying DC591017's effects in IPF.
- To assess DC591017's impact on the lung microenvironment using lung-on-a-chip models.
Main Methods:
- In vivo studies using a bleomycin (BLM)-induced mouse model of pulmonary fibrosis.
- In vitro cellular studies involving lung fibroblasts, epithelial cells, and macrophages.
- Lung-on-a-chip models to investigate cell-cell interactions in the lung microenvironment.
Main Results:
- Oral DC591017 (10 mg/kg) significantly improved lung function, reduced fibrosis, and mitigated weight loss in mice, comparable to nintedanib.
- DC591017 inhibited fibroblast activation, migration, and epithelial-mesenchymal transition (EMT).
- DC591017 modulated macrophage polarization (M2) and reduced dendritic cell infiltration, impacting the macrophage-fibroblast-epithelial cell microenvironment.
Conclusions:
- DC591017 demonstrates potent anti-fibrotic activity in IPF models.
- The drug's efficacy stems from modulating interactions among multiple pathological cell types.
- DC591017 represents a promising therapeutic candidate for IPF treatment.
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