Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes

Our plain-English summary of Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes, by T.C. Vandivort, T.P. Birkland, T.P. Domiciano, et al (International Journal of Nanomedicine, 2017).

The study

• Authors: T.C. Vandivort, T.P. Birkland, T.P. Domiciano, S. Mitra, T.J. Kavanagh, W.C. Parks
• Journal: International Journal of Nanomedicine
• Published: 2017;12:1019-1031
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Multiwalled carbon nanotubes (MWCNTs) are nanomaterials composed of multiple layers of graphene cylinders with unique properties that make them valuable for a number of industries. However, rising global production has led to concerns regarding potential occupational exposures to them as raw materials during handling. This is especially true for long MWCNT fibers, whose aspect ratio has been posited to initiate pathology similar to that of asbestos. Matrix metalloproteinases (MMPs) are a class of extracellular endopeptidases that control various processes related to tissue repair, inflammation, and more. Stromelysin-2 (MMP-10) has roles in modulating macrophage activation and function, and hence, we used an MMP-10 null (Mmp10-/-) mouse model to assess its role in controlling lung responses to inhaled long MWCNTs. Oropharyngeal aspiration of long MWCNTs (80 µg/mouse) by wild-type mice induced expression of Mmp10 mRNA, which was accompanied by a robust inflammatory response characterized by elevated expression of Tnfa, Il6, and Il1b. In Mmp10-/- mice, we found that absence of MMP-10 led to impaired pulmonary clearance of MWCNTs and reduced macrophage cell survival. Exposure of wild-type bone marrow-derived macrophages (BMDMs) and alveolar macrophages to MWCNTs caused a rapid, dose-dependent upregulation of Mmp10 mRNA expression, which was accompanied by expression of pro-inflammatory products (Il6 and Il1b). These products were further enhanced in Mmp10-/- macrophages, resulting in increased caspase-3-dependent cell death compared with wild-type cells. These findings indicate that MMP-10 facilitates the clearance of MWCNTs and moderates the pro-inflammatory response of exposed alveolar and infiltrated macrophages.

In plain English

This was a laboratory study in mice and cultured mouse macrophages testing what stromelysin-2 (MMP-10) does after exposure to long multiwalled carbon nanotubes (MWCNTs), which the authors note have been posited to initiate asbestos-like pathology. Wild-type and MMP-10 null (Mmp10-/-) mice received 80 µg of MWCNTs in 50 µL dispersion medium (n=6 per genotype), or medium alone (n=3), by oropharyngeal aspiration, with lungs and lavage examined 24 hours later (the methods state six per exposure group). In wild-type lungs, MWCNTs raised Mmp10 mRNA about 3-fold above dispersion-medium controls, with increased Il6 and Nos2 mRNA. Mmp10-/- mice had significantly fewer macrophages in lavage, about 2.5-fold more retained nanotube aggregates, and about a 2-fold increase in caspase-3 activity in lavage cells compared with wild-type. Cultured Mmp10-/- bone marrow-derived macrophages showed higher Il1b, Tnfa, Il6 and Il12a transcripts, more IL-1beta release and more caspase-3 activity than wild-type; in alveolar macrophages greater IL-1beta release was only a trend (P=0.161), while caspase-3 activity rose nearly 3-fold. The authors concluded that MMP-10 promotes clearance of MWCNTs and moderates macrophage inflammation and death.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Controlled animal experiment in wild-type and Mmp10-null mice with accompanying macrophage cell-culture experiments
• Who was studied: Mmp10-/- mice on a C57BL/6J background and wild-type littermates (male and female, 8-12 weeks old); Figure 1 states n=6 per genotype for MWCNT exposure and n=3 for dispersion-medium controls, while the methods state 6 per exposure group per genotype; plus bone marrow-derived and alveolar macrophages from these mice; University of Washington and Cedars-Sinai Medical Center
• Exposure: Long multiwalled carbon nanotubes, 80 µg per mouse in 50 µL dispersion medium by oropharyngeal aspiration in vivo; 10-100 µg/mL for 2-24 h on bone marrow-derived macrophages and 100 µg/mL on alveolar macrophages in vitro; tubes 10-20 nm outer diameter, 10-30 µm length, 95.8%±0.6% carbon with trace Ni and Fe
• Main results:
  • In wild-type lungs, MWCNT exposure increased Mmp10 mRNA about 3-fold over dispersion-medium controls
  • After MWCNTs, total lavage cells fell relative to controls and were significantly lower in Mmp10-/- mice; macrophage percentage and number were reduced and neutrophil percentage higher in Mmp10-/- lavage than wild-type
  • Total neutrophil numbers, though raised by MWCNTs, did not differ significantly between genotypes; only the macrophage reduction was statistically significant
  • Lung Il6 and Nos2 mRNA were increased in MWCNT-treated mice
  • Lung Il6 and Nos2 levels did not differ between genotypes; whole-lung Il1b only trended upward without reaching significance and Tnfa was unaffected
  • About 2.5-fold more retained MWCNT particles were measured in Mmp10-/- lungs
  • A greater percentage of total lung tissue was occupied by MWCNTs in Mmp10-/- lungs than in wild-type lungs
  • Per-cell uptake of MWCNTs did not differ between genotypes in vivo or in culture
  • Caspase-3 activity was unchanged in whole lung lysates but about 2-fold higher in lavage cells from MWCNT-treated Mmp10-/- mice than wild-type
  • In bone marrow-derived macrophages, MWCNTs stimulated Il1b, Il6, Il12a and Tnfa mRNA in wild-type cells, with higher levels in Mmp10-/- cells
  • IL-1beta protein release from bone marrow-derived macrophages was induced by MWCNTs and significantly increased in Mmp10-/- cells
  • Caspase-3 activity after MWCNT exposure was significantly greater in Mmp10-/- bone marrow-derived macrophages than wild-type
  • In alveolar macrophages, MWCNTs did not change caspase-3 activity in wild-type cells but produced nearly a 3-fold increase in Mmp10-/- cells; the greater IL-1beta release from Mmp10-/- cells was a trend (P=0.161)
• The authors' conclusion: The authors concluded that MMP-10 facilitates clearance of MWCNTs from the lung and moderates the pro-inflammatory response and apoptosis of alveolar and infiltrating macrophages
• Limitations the authors state:
  • The authors state the doses used were higher than expected occupational exposures
  • The authors state their bone marrow-derived macrophage data do not fully support the explanation that increased macrophage apoptosis causes the reduced clearance
  • The authors state the mechanism and the substrate on which MMP-10 acts are not yet known
  • The authors state the long-term impact of MMP-10 on responses to MWCNT exposure remains open

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Occupational Exposure, Aspect Ratio (Length-to-diameter ratio), Pathology, Macrophage, Alveolar Macrophage.

Related studies

• A comparison of acute and long-term effects of industrial multiwalled carbon nanotubes on human lung and immune cells in vitro — T. Thurnherr, C. Brandenberger, et al. (2011)
• Multiwalled carbon nanotube-induced pulmonary inflammatory and fibrotic responses and genomic changes following aspiration exposure in mice: A 1-year postexposure study — B.N. Snyder-Talkington, C. Dong, et al. (2016)
• Inflammation in the pleural cavity following injection of multi-walled carbon nanotubes is dependent on their characteristics and the presence of IL-1 genes — Y.J. Arnoldussen, V. Skaug, et al. (2018)
• Persistent Pleural Lesions and Inflammation by Pulmonary Exposure of Multiwalled Carbon Nanotubes — D. Liao, Q. Wang, et al. (2018)
• Carbon nanotubes induce inflammation but decrease the production of reactive oxygen species in lung — D. Crouzier, S. Follot, et al. (2010)
• Inhalation and Oropharyngeal Aspiration Exposure to Rod-Like Carbon Nanotubes Induce Similar Airway Inflammation and Biological Responses in Mouse Lungs — P. Kinaret, M. Ilves, et al. (2017)

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