Inflammation in the pleural cavity following injection of multi-walled carbon nanotubes is dependent on their characteristics and the presence of IL-1 genes

Our plain-English summary of Inflammation in the pleural cavity following injection of multi-walled carbon nanotubes is dependent on their characteristics and the presence of IL-1 genes, by Y.J. Arnoldussen, V. Skaug, M. Aleksandersen, et al (Nanotoxicology, 2018).

The study

• Authors: Y.J. Arnoldussen, V. Skaug, M. Aleksandersen, E. Ropstad, K.H. Anmarkrud, E. Einarsdottir, F. Chin-Lin, C. Granum Bjørklund, M. Kasem, E. Eilertsen, R.N. Apte, S. Zienolddiny
• Journal: Nanotoxicology
• Published: 2018;12(6):522-538
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Upon inhalation, multi-walled carbon nanotubes (MWCNTs) may reach the subpleura and pleural spaces, and induce pleural inflammation and/or mesothelioma in humans. However, the mechanisms of MWCNT-induced pathology after direct intrapleural injections are still only partly elucidated. In particular, a role of the proinflammatory interleukin-1 (IL-1) cytokines in pleural inflammation has so far not been published. We examined the MWCNT-induced pleural inflammation, gene expression abnormalities, and the modifying role of IL-1α and β cytokines following intrapleural injection of two types of MWCNTs (CNT-1 and CNT-2) compared with crocidolite asbestos in IL-1 wild-type (WT) and IL-1α/β KO (IL1-KO) mice. Histopathological examination of the pleura 28 days post-exposure revealed mesothelial cell hyperplasia, leukocyte infiltration, and fibrosis occurring in the CNT-1 (Mitsui-7)-exposed group. The pleura of these mice also showed the greatest changes in mRNA and miRNA expression levels, closely followed by CNT-2. In addition, the CNT-1-exposed group also presented the greatest infiltrations of leukocytes and proliferation of fibrous tissue. WT mice were more prone to development of sustained inflammation and fibrosis than IL1-KO mice. Prominent differences in genetic and epigenetic changes were also observed between the two genotypes. In conclusion, the fibrotic response to MWCNTs in the pleura depends on the particles' physico-chemical properties and on the presence or absence of the IL-1 genes. Furthermore, we found that CNT-1 was the most potent inducer of inflammatory responses, followed by CNT-2 and crocidolite asbestos.

In plain English

This was an animal experiment in mice. The authors injected two types of multi-walled carbon nanotubes, CNT-1 (Mitsui-7) and CNT-2 (n-Tec), or UICC crocidolite asbestos, at two dose levels, directly into the pleural space of the chest. They used normal (wild-type) mice and mice lacking the genes for the inflammatory signals IL-1 alpha and beta. Groups had six or seven mice, and control mice received the dispersion liquid alone. After 28 days the pleura and lungs were examined under the microscope and tested for gene activity. Pleural fibrosis was significantly increased in all exposed groups compared with controls. CNT-1 caused the most severe lesions, with the highest average scores on a 0 to 4 scale for inflammatory cells (3.1), granulomas (3.6) and fibrosis (3.6). Crocidolite and CNT-2 scored similarly to each other. Higher doses generally gave higher scores. Mice lacking IL-1 had less inflammatory cell infiltration than normal mice. The authors ranked CNT-1 above CNT-2 and crocidolite asbestos. They stated that the findings cannot be directly extrapolated to humans.

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: Animal experiment: single intrapleural injection in mice, with examination 28 days later (histopathology plus mRNA and miRNA expression)
• Who was studied: C57BL/6 mice, both wild-type (WT) and IL-1 alpha/beta double knockout (IL1-KO), in groups of six or seven per exposure, studied at the Norwegian University of Life Sciences in Oslo, Norway
• Exposure: Injection through the right chest wall into the pleural space of dispersion medium alone (sham), or medium containing one of two dose levels (printed as 50 or 100; the unit symbol is garbled) of CNT-1 (Mitsui-7), CNT-2 (n-Tec), or UICC crocidolite asbestos
• Main results:
  • Pleural fibrosis was significantly increased in all exposed groups (CNT-1, CNT-2, crocidolite) compared with controls
  • Average pleural scores (0 to 4 scale), all mice combined regardless of genotype: CNT-1 scored 3.1 for inflammatory cells, 3.6 for granulomas and 3.6 for fibrosis. Crocidolite scored 2.4, 1.2 and 2.2. CNT-2 scored 2.2, 1.8 and 2.4. Controls scored 0.0. CNT-1 differed significantly from the others; crocidolite and CNT-2 shared the same significance letter on these three measures.
  • Pleural lesions were more severe in CNT-1-exposed animals and milder in the CNT-2 and asbestos groups. Granulomas were more numerous in the CNT-1 groups.
  • The visceral pleura showed multifocal mesothelial cell hyperplasia in all exposed animals
  • IL1-KO mice had less inflammatory cell infiltration in the pleura than WT mice. Granulomas did not differ significantly between the two genotypes.
  • Dose mattered: high-dose animals generally showed higher scores for granulomas, fibrosis, inflammatory cells and fibers in the pleura
  • At gross examination, the asbestos-exposed animals had the least visible changes, and the high-dose CNT-1 groups were the most affected
  • In the pleura of WT mice, CNT-1 had the largest effect on fibrosis-related gene expression and asbestos the lowest. Particle exposures caused less significant changes in IL1-KO mice.
• The authors' conclusion: The authors concluded that IL-1 partly plays a role in the fibrotic response to the nanotubes. Based on ability to induce pathologic and genetic changes, they ranked CNT-1 first, followed by CNT-2 and crocidolite asbestos. They stated that the study strengthens the hypothesis of similarities between these nanotubes and asbestos in the pleural space.
• Limitations the authors state:
  • The findings cannot be directly extrapolated to humans
  • The doses may not be comparable to workplace exposures
  • High doses injected directly into the pleural space may cause nonspecific effects, acute inflammation, tissue injury, and unspecific genetic and epigenetic changes
  • The study was too short to identify predictive markers of tumor development
  • Fibers in pleural fluid were not examined by electron microscopy after death

Topics

The National Library of Medicine indexes this study under subjects our site covers: Crocidolite.

Medical terms in this study, explained in our Lexicon: Inflammation, Pleural Cavity, Mesothelioma, Pathology, Cytokine, Crocidolite, Pleura, Mesothelial Cells.

Related studies

• Length-dependent retention of carbon nanotubes in the pleural space of mice initiates sustained inflammation and progressive fibrosis on the parietal pleura — F.A. Murphy, C.A. Poland, et al. (2011)
• Multi-walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats — J. Xu, M. Futakuchi, et al. (2012)
• Size- and shape-dependent pleural translocation, deposition, fibrogenesis, and mesothelial proliferation by multiwalled carbon nanotubes — J. Xu, D.B. Alexander, et al. (2014)
• Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes — T.C. Vandivort, T.P. Birkland, et al. (2017)
• Persistent Pleural Lesions and Inflammation by Pulmonary Exposure of Multiwalled Carbon Nanotubes — D. Liao, Q. Wang, et al. (2018)
• Epithelial-mesenchymal transition involved in pulmonary fibrosis induced by multi-walled carbon nanotubes via TGF-beta/Smad signaling pathway — T. Chen, H. Nie, et al. (2014)

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