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Published on: October 28, 2022
TAK1 inhibition attenuates both inflammation and fibrosis in experimental pneumoconiosis
Jie Li1, Chao Liang2,3, Zong-Kang Zhang1
1School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Sha Tin, Hong Kong SAR, China.
Abstract:
Pneumoconiosis, caused by inhalation of mineral dusts, is a major occupational disease worldwide. Currently, there are no effective drugs owing to a lack of potential therapeutic targets during either the inflammation or fibrosis molecular events in pneumoconiosis. Here, we performed microarrays to identify aberrantly expressed genes in the above molecular events in vitro and found a hub gene transforming growth factor-β-activated kinase 1 (TAK1), which was highly expressed and activated in pneumoconiosis patients as well as silica-exposed rats with experimental pneumoconiosis. Genetic modulation of TAK1 by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9, RNA interference and overexpression indicated the important role of TAK1 in both inflammation and fibrosis in experimental pneumoconiosis. To achieve pharmacological TAK1 inhibition, we virtually screened out a natural product resveratrol, which targeted TAK1 at both N161 and A107 residues, and significantly inhibited TAK1 activation to attenuate inflammation and fibrosis in vitro. Consistently, in vivo prevention and intervention studies showed that resveratrol could inhibit pulmonary inflammation and fibrosis in silica-exposed rats.
Insights
Pneumoconiosis, a lung disease from mineral dust, lacks treatments. This study identifies transforming growth factor-β-activated kinase 1 (TAK1) as a key target, with resveratrol showing promise in inhibiting inflammation and fibrosis.
Area of Science:
- Occupational Health
- Pulmonary Medicine
- Molecular Biology
Background:
- Pneumoconiosis is a significant global occupational disease with no effective treatments.
- Current therapeutic strategies are limited by a lack of identified molecular targets for inflammation and fibrosis.
Purpose of the Study:
- To identify key molecular targets involved in pneumoconiosis pathogenesis.
- To evaluate the therapeutic potential of resveratrol in inhibiting inflammation and fibrosis associated with pneumoconiosis.
Main Methods:
- Microarray analysis to identify differentially expressed genes in pneumoconiosis models.
- Genetic manipulation of transforming growth factor-β-activated kinase 1 (TAK1) using CRISPR/Cas9 and RNA interference.
- In vitro and in vivo studies using cell cultures and silica-exposed rat models.
- Virtual screening to identify natural products targeting TAK1.
Main Results:
- TAK1 was identified as a hub gene, highly expressed and activated in pneumoconiosis.
- Genetic modulation confirmed TAK1's critical role in pneumoconiosis-related inflammation and fibrosis.
- Resveratrol was identified as a natural product inhibitor of TAK1, targeting specific residues (N161 and A107).
- Resveratrol treatment attenuated inflammation and fibrosis in vitro and in vivo in silica-exposed rats.
Conclusions:
- TAK1 is a crucial therapeutic target for pneumoconiosis.
- Resveratrol demonstrates significant potential as a therapeutic agent for inhibiting pneumoconiosis progression by targeting TAK1.
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