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Cited by 16Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisOccupational and environmental lung diseasesSystemic Sclerosis and Related Diseases

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A Novel N-Arylpyridone Compound Alleviates the Inflammatory and Fibrotic Reaction of Silicosis by Inhibiting the ASK1-p38 Pathway and Regulating Macrophage Polarization

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Fan, Mingming, Xiao, Huijuan, Song, Dingyun, Zhu, Lili, Zhang, Jie, Zhang, Xinran, Wang, Jing, Dai, Huaping, Wang, Chen·2022·Frontiers in Pharmacology
DOI 10.3389/fphar.2022.848435PMC PMC8983992
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Abstract

Silicosis is one of the potentially fatal occupational diseases characterized by respiratory dysfunction, chronic interstitial inflammation, and fibrosis, for which treatment options are limited. Previous studies showed that a novel N-arylpyridone compound named AKEX0011 exhibited anti-inflammatory and anti-fibrotic effects in bleomycin-induced pulmonary fibrosis; however, it is unknown whether it could also be effective against silicosis. Therefore, we sought to investigate the preventive and therapeutic roles of AKEX0011 in a silicosis rodent model and in a silica-stimulated macrophage cell line. In vivo , our results showed that AKEX0011 ameliorated silica-induced imaging lung damages, respiratory dysfunction, reduced the secretion of inflammatory and fibrotic factors (TNF-α, IL-1β, IL-6, TGF-β, IL-4, and IL-10), and the deposition of fibrosis-related proteins (collagen I, fibronectin, and α-SMA), regardless of early or advanced therapy. Specifically, we found that AKEX0011 attenuated silicosis by inhibiting apoptosis, blocking the ASK1-p38 MAPK signaling pathway, and regulating polarization of macrophages. In vitro , AKEX0011 inhibited macrophages from secreting inflammatory cytokines and inhibited apoptosis of macrophages in pre-treated and post-treated models, concurrent with blocking the ASK1-p38 pathway and inhibiting M1 polarization. Collectively, AKEX0011, as a novel N-arylpyridone compound, exerted protective effects for silica-induced pulmonary inflammation and fibrosis both in vivo and in vitro , and hence, it could be a strong drug candidate for the treatment of silicosis.

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  • ASK1, an upstream kinase that activates JNK1/2-p38 signaling during inflammation and fibrosis progression, plays a vital role in the M1 polarization of macrophages.

    “ASK1, an upstream kinase that activates JNK1/2-p38 signaling during inflammation and fibrosis progression, plays a vital role in the M1 polarization of macrophages.39,40”

    From Sphingosine Kinase 1 Aggravates Liver Fibrosis by Mediating Macrophage Recruitment and Polarization (2024) · cites this paper as [39]

    The Results section on silicosis models identifies ASK1 as an upstream activator of p38 and links ASK1–p38 signaling to inflammation and fibrosis (page not provided). The macrophage Results report that treatment blocked ASK1–p38 signaling and reduced M1 polarization, but attribute the M1 effect to NF-κB signaling. Our copy does not establish JNK1/2 activation or that ASK1 itself plays a vital role in M1 polarization. (LLM, conf=0.86)

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Research works printed but not linked: 40

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Metadata

Authors
Fan, M., Xiao, H., Song, D., Zhu, L., Zhang, J., Zhang, X., Wang, J., Dai, H., & Wang, C.
Affiliations
  • Capital Medical University (CN)
  • Jilin University (CN)
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
Corresponding author
  • Wang, Jing
  • Dai, Huaping
  • Wang, Chen
ORCID
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2022-03-23
Volume
13
Pages
848435-848435
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2022.848435
PMC
PMC8983992
OpenAlex
W4220990758
Cited by
16
References
1
Citations by year
2025: 4 · 2024: 5 · 2023: 5 · 2022: 2
FWCI
2.58
Type
journal article
Language
en
Update notices
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Greater South Information System
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
  • Health Sciences › Medicine › Rheumatology › Systemic Sclerosis and Related Diseases
Keywords
silicosis, macrophage polarization, M1 macrophage polarization, pulmonary fibrosis, lung inflammation, silica-induced lung injury, anti-inflammatory activity, antifibrotic effect, macrophage apoptosis, inflammatory cytokines, collagen deposition

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