Related Experiment Video
Updated: Mar 3, 2026
A Mouse Model of Pulmonary Fibrosis Induced by Nasal Bleomycin Nebulization
Published on: January 20, 2023
MLN4924 protects against bleomycin-induced pulmonary fibrosis by inhibiting the early inflammatory process
Qi Deng1,2, Jiaojiao Zhang1, Yaqun Gao3
1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University500 Dongchuan Road, Shanghai 200241, China.
Abstract:
Pulmonary fibrosis is a complex pathological process characterized by massive destruction of the structure of lung tissues and aggravated pulmonary function impairment. The underlying mechanisms of pulmonary fibrosis are incompletely understood and therefore limited treatment options are available currently. Here, we report that MLN4924, an NEDD8 activation enzyme (NAE) activity-inhibiting molecule, blocks the maintenance and progression of established pulmonary fibrosis. We found that MLN4924 acts against bleomycin-induced pulmonary fibrosis mainly at the early inflammatory stage. Pharmacologically targeting the neddylation of Cullin-Ring E3 ligase (CRL) by MLN4924, significantly abrogated NF-κB responses, suppressed MAPK activity, and reduced secretion of TNF-α-elicited pro-inflammatory cytokines and MCP1-induced chemokines. MLN4924 inhibited pro-inflammatory responses while maintaining or increasing the production of the anti-inflammatory mediators such as anti-inflammatory interleukins (ILs) following bleomycin administration, which is closely correlated to its blocking NF-κB-mediated signaling. Consistently, our studies identified MLN4924 as a promising therapeutic drug for pulmonary fibrosis and suggested a potential role of MLN4924 that fine tunes the MAPK signaling pathway controlling the inflammatory reactions at the early stages of pulmonary fibrosis. In addition, our findings may broaden the potential practical application of MLN4924 as an effective therapeutic strategy against other inflammation-associated diseases.
Insights
MLN4924, a novel drug, effectively halts pulmonary fibrosis progression by targeting early inflammation. It inhibits pro-inflammatory responses while promoting anti-inflammatory mediators, offering a promising therapeutic strategy for lung diseases.
Area of Science:
- Pulmonology
- Pharmacology
- Immunology
Background:
- Pulmonary fibrosis involves lung tissue destruction and impaired function.
- Current treatment options for pulmonary fibrosis are limited due to incomplete understanding of its mechanisms.
Purpose of the Study:
- To investigate the therapeutic potential of MLN4924 in established pulmonary fibrosis.
- To elucidate the mechanisms by which MLN4924 impacts fibrotic processes and inflammation.
Main Methods:
- Utilized bleomycin-induced pulmonary fibrosis model in preclinical studies.
- Administered MLN4924 to assess its effects on inflammatory markers and signaling pathways.
- Analyzed the modulation of NF-κB, MAPK, and cytokine secretion.
Main Results:
- MLN4924 effectively blocked the maintenance and progression of pulmonary fibrosis, particularly at the early inflammatory stage.
- Targeting neddylation of Cullin-Ring E3 ligase (CRL) with MLN4924 abrogated NF-κB responses and suppressed MAPK activity.
- MLN4924 reduced pro-inflammatory cytokines (e.g., TNF-α) and chemokines (e.g., MCP1) while preserving anti-inflammatory mediators (e.g., ILs).
Conclusions:
- MLN4924 demonstrates significant therapeutic potential for pulmonary fibrosis by modulating inflammatory signaling pathways.
- The drug's ability to fine-tune MAPK signaling and inhibit NF-κB-mediated responses is crucial for its efficacy.
- Findings suggest MLN4924 could be a valuable treatment for pulmonary fibrosis and other inflammation-associated diseases.
