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Cited by 24Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisOccupational and environmental lung diseasesNanoparticles: synthesis and applications

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MMP-3-mediated cleavage of OPN is involved in copper oxide nanoparticle-induced activation of fibroblasts

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Zhang, Yuanbao, Mo, Yiqun, Zhang, Yue, Yuan, Jiali, Zhang, Qunwei·2023·Particle and Fibre Toxicology
DOI 10.1186/s12989-023-00532-yPMC PMC10201731
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Abstract

Background: Copper oxide nanoparticles (Nano-CuO) are one of the most produced and used nanomaterials. Previous studies have shown that exposure to Nano-CuO caused acute lung injury, inflammation, and fibrosis. However, the mechanisms underlying Nano-CuO-induced lung fibrosis are still unclear. Here, we hypothesized that exposure of human lung epithelial cells and macrophages to Nano-CuO would upregulate MMP-3, which cleaved osteopontin (OPN), resulting in fibroblast activation and lung fibrosis. Methods: A triple co-culture model was established to explore the mechanisms underlying Nano-CuO-induced fibroblast activation. Cytotoxicity of Nano-CuO on BEAS-2B, U937* macrophages, and MRC-5 fibroblasts were determined by alamarBlue and MTS assays. The expression or activity of MMP-3, OPN, and fibrosis-associated proteins was determined by Western blot or zymography assay. Migration of MRC-5 fibroblasts was evaluated by wound healing assay. MMP-3 siRNA and an RGD-containing peptide, GRGDSP, were used to explore the role of MMP-3 and cleaved OPN in fibroblast activation. Results: Exposure to non-cytotoxic doses of Nano-CuO (0.5 and 1 µg/mL) caused increased expression and activity of MMP-3 in the conditioned media of BEAS-2B and U937* cells, but not MRC-5 fibroblasts. Nano-CuO exposure also caused increased production of cleaved OPN fragments, which was abolished by MMP-3 siRNA transfection. Conditioned media from Nano-CuO-exposed BEAS-2B, U937*, or the co-culture of BEAS-2B and U937* caused activation of unexposed MRC-5 fibroblasts. However, direct exposure of MRC-5 fibroblasts to Nano-CuO did not induce their activation. In a triple co-culture system, exposure of BEAS-2B and U937* cells to Nano-CuO caused activation of unexposed MRC-5 fibroblasts, while transfection of MMP-3 siRNA in BEAS-2B and U937* cells significantly inhibited the activation and migration of MRC-5 fibroblasts. In addition, pretreatment with GRGDSP peptide inhibited Nano-CuO-induced activation and migration of MRC-5 fibroblasts in the triple co-culture system. Conclusions: Our results demonstrated that Nano-CuO exposure caused increased production of MMP-3 from lung epithelial BEAS-2B cells and U937* macrophages, which cleaved OPN, resulting in the activation of lung fibroblasts MRC-5. These results suggest that MMP-3-cleaved OPN may play a key role in Nano-CuO-induced activation of lung fibroblasts. More investigations are needed to confirm whether these effects are due to the nanoparticles themselves and/or Cu ions.

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Metadata

Authors
Zhang, Y., Mo, Y., Zhang, Y., Yuan, J., & Zhang, Q.
Affiliations
  • Northwestern University (US)
  • University of Louisville (US)
Corresponding author
Zhang, Qunwei
ORCID
Venue
Particle and Fibre Toxicology
Publisher
Springer Science and Business Media LLC
Published
2023-05-22
Volume
20
Issue
1
Pages
22-22
ISSN
1743-8977 (ISSN-L)
DOI
10.1186/s12989-023-00532-y
PMC
PMC10201731
OpenAlex
W4377291875
Cited by
24
References
2
Citations by year
2026: 5 · 2025: 10 · 2024: 9
FWCI
4.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Particle and Fibre Toxicology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institutes of Health (ES023696)
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
  • Physical Sciences › Materials Science › Materials Chemistry › Nanoparticles: synthesis and applications
Keywords
copper oxide nanoparticles, MMP-3, fibroblast activation, pulmonary fibrosis, nanoparticle toxicity, macrophages, lung epithelial cells, fibroblast migration, RGD peptide, lung injury, GRGDSP peptide, GRGDS peptide
MeSH terms
Cell Line, Copper, Epithelial Cells, Fibroblasts, Humans, Lung, Macrophages, Coculture Techniques, Matrix Metalloproteinase 3, Osteopontin, Metal Nanoparticles

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