The threshold length for fiber-induced acute pleural inflammation: shedding light on the early events in asbestos-induced mesothelioma

Our plain-English summary of The threshold length for fiber-induced acute pleural inflammation: shedding light on the early events in asbestos-induced mesothelioma, by A. Schinwald, F.A. Murphy, A. Prina-Mello, et al (Toxicological Sciences, 2012).

The study

• Authors: A. Schinwald, F.A. Murphy, A. Prina-Mello, C.A. Poland, F. Byrne, D. Movia, J.R. Glass, J.C. Dickerson, D.A. Schultz, C.E. Jeffree, W. Macnee, K. Donaldson
• Journal: Toxicological Sciences
• Published: 2012;128(2):461-70
• Cited by: 125 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Suspicion has been raised that high aspect ratio nanoparticles or nanofibers might possess asbestos-like pathogenicity. The pleural space is a specific target for disease in individuals exposed to asbestos and by implication of nanofibers. Pleural effects of fibers depends on fiber length, but the key threshold length beyond which adverse effects occur has never been identified till now because all asbestos and vitreous fiber samples are heterogeneously distributed in their length. Nanotechnology advantageously allows for highly defined length distribution of synthetically engineered fibers that enable for in-depth investigation of this threshold length. We utilized the ability to prepare silver nanofibers of five defined length classes to demonstrate a threshold fiber length for acute pleural inflammation. Nickel nanofibers and carbon nanotubes were then used to strengthen the relationship between fiber length and pleural inflammation. A method of intrapleural injection of nanofibers in female C57Bl/6 strain mice was used to deliver the fiber dose, and we then assessed the acute pleural inflammatory response. Chest wall sections were examined by light and scanning electron microscopy to identify areas of lesion; furthermore, cell-nanowires interaction on the mesothelial surface of the parietal pleura in vivo was investigated. Our results showed a clear threshold effect, demonstrating that fibers beyond 4 µm in length are pathogenic to the pleura. The identification of the threshold length for nanofiber-induced pathogenicity in the pleura has important implications for understanding the structure-toxicity relationship for asbestos-induced mesothelioma and consequent risk assessment with the aim to contribute to the engineering of synthetic nanofibers by the adoption of a benign-by-design approach.

In plain English

This was a laboratory experiment in mice designed to find the threshold fiber length for acute inflammation in the pleural cavity. The authors injected 5 µg of material directly into the pleural cavity of 9-week-old female C57Bl/6 mice (n = 4 per group) and lavaged the cavity 24 hours and 1 week later. They compared silver nanowires in five tight length classes (mean 3, 5, 10, 14 and 28 µm), nickel nanowires (4 and 20 µm), multiwalled carbon nanotubes (2, 13 and 36 µm), compact silver, nickel and carbon black nanoparticles, and long fiber and short fiber amosite asbestos; the carbon black, 2 µm and 36 µm nanotube data were taken from an earlier paper by Murphy et al. (2011). At 24 hours, silver nanowires of 5 µm and longer, long fiber amosite, the longer nanotubes and the 20 µm nickel nanowires raised total cell and granulocyte counts, while the 3 µm silver nanowires, short fiber amosite, 2 µm nanotubes, 4 µm nickel nanowires and compact particles produced no significant increase. Sections of the parietal pleura showed large lesions after long fiber amosite and after silver nanowires of 5 µm and longer, but not after the 3 µm silver nanowires or short fiber amosite. The authors concluded the threshold length is 5 µm in the mouse.

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: intrapleural injection of nanofibers and asbestos in mice, with pleural lavage, histology and electron microscopy
• Who was studied: Nine-week-old female C57Bl/6 mice, 4 per treatment group for lavage (2 per treatment for chest wall sections), studied in a UK Home Office approved facility
• Exposure: Single intrapleural dose of 5 µg per mouse of silver nanowires of five mean lengths (3, 5, 10, 14, 28 µm), nickel nanowires (4 and 20 µm), multiwalled carbon nanotubes (2, 13, 36 µm), long fiber and short fiber amosite asbestos, and compact nanoparticle controls (silver, nickel, carbon black)
• Main results:
  • At 24 hours, silver nanowires of 5 µm and longer and long fiber amosite increased total cells and granulocytes; the 3 µm silver nanowires, short fiber amosite and compact silver nanoparticles did not cause significant inflammation
  • Granulocyte response did not differ significantly between AgNW5, AgNW10 and AgNW14, but AgNW28 gave a significantly higher response than AgNW5
  • AgNW3 caused no significant rise in inflammatory cells even at a dose of 10 µg per mouse
  • Parietal pleura at 24 hours was normal after vehicle, short fiber amosite, silver nanoparticles and AgNW3, but showed large lesions of macrophages and granulocytes after long fiber amosite and AgNW5/10/14/28
  • Across the other fiber types, no significant increase in total cells or granulocytes occurred with particulates and short fibers (NPCB, Ni-P, Ag-P, SFA, NT2, AgNW3, NiNW4), while all samples 5 µm and longer produced an inflammatory response
  • Some of the comparison data in the combined figure (carbon black nanoparticles, 2 µm and 36 µm nanotubes) were taken from an earlier paper rather than generated in this experiment
  • AgNW3 and AgNW5 were mostly fully taken up by pleural macrophages, whereas AgNW10/14/28 led to frustrated phagocytosis
  • At 7 days the acute inflammation had largely resolved, with a length-dependent effect still detectable for AgNW14/28
• The authors' conclusion: The authors concluded that their data give a quantitative threshold length of 5 µm in the mouse for fiber-induced pleural inflammation, which they suggest can be extrapolated to humans, and that short fibers less than 5 µm could form the basis of safer-by-design nanofibers
• Limitations the authors state:
  • The work was done in a mouse model with a restricted range of nanofibers, and the authors state extrapolation to humans is not straightforward
  • It measured only a short-term response
  • The threshold conclusion is based mainly on straight single fibers
  • Measurements of soluble silver release were confounded by silver chloride formation, so those data were not included
  • The authors note a high enough dose of shorter fibers could still be inflammogenic through aggregation and clogging of stomata
  • The silver nanowires were not biopersistent beyond a few days

Topics

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

Medical terms in this study, explained in our Lexicon: Inflammation, Mesothelioma, Aspect Ratio (Length-to-diameter ratio), Fiber Length, Vitreous, Scanning Electron Microscopy (SEM), Parietal Pleura, Pleura.

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• The mechanism of pleural inflammation by long carbon nanotubes: interaction of long fibres with macrophages stimulates them to amplify pro-inflammatory responses in mesothelial cells — F.A. Murphy, A. Schinwald, et al. (2012)
• 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)
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