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Efficient Elimination of Inhaled Nanoparticles from the Alveolar Region: Evidence for Interstitial Uptake and Subsequent Reentrainment onto Airways Epithelium

Semmler-Behnke, Manuela, Takenaka, Shinji, Fertsch, Steffanie, Wenk, Alexander, Seitz, Jürgen, Mayer, Paula, Oberdörster, Günter, Kreyling, Wolfgang G.·2007·Environmental Health Perspectives
DOI 10.1289/ehp.9685PMC PMC1867986
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Abstract

Background: There is ongoing discussion that inhaled nanoparticles (NPs, < 100 nm) may translocate from epithelial deposition sites of the lungs to systemic circulation. Objectives and Methods: We studied the disappearance of NPs from the epithelium by sequential lung retention and clearance and bronchoalveolar lavage (BAL) measurements in healthy adult Wistar Kyoto (WKY) rats at various times over 6 months after administration of a single 60- to 100-min intratracheal inhalation of iridium-192 (192Ir)–radiolabeled NPs. A complete 192Ir balance of all organs, tissues, excretion, remaining carcass, and BAL was performed at each time point. Results: Directly after inhalation we found free NPs in the BAL; later, NPs were predominantly associated with alveolar macropages (AMs). After 3 weeks, lavageable NP fractions decreased to 0.06 of the actual NP lung burden. This is in stark contrast to the AM-associated fraction of micron-sized particles reported in the literature. These particles remained constant at about 0.8 throughout a 6-month period. Three weeks after inhalation, 80% of the retained Ir NPs was translocated into epithelium and interstitium. Conclusion: There is a strong size-selective difference in particle immobilization. Furthermore, AM-mediated NP transport to the larynx originates not only from the NP fraction retained on the epithelium but also from NPs being reentrained from the interstitium to the luminal side of epithelium. We conclude that NPs are much less phagocytized by AMs than large particles but are effectively removed from the lung surface into the interstitium. Even from these interstitial sites, they undergo AM-mediated long-term NP clearance to the larynx.

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Figure 1 (A) SPECT gamma camera (Prism 2000; Philips) image of 192Ir activity distribution in the dried lungs applying a pinhole collimation geometry. (B) Air-dried rat lungs, immediately removed after inhalation and air dried at total lung capacity, dorsal view; bar = 10 mm.
Figure 1 (A) SPECT gamma camera (Prism 2000; Philips) image of 192Ir activity distribution in the dried lungs applying a pinhole collimation geometry. (B) Air-dried rat lungs, immediately removed after inhalation and air dried at total lung capacity, dorsal view; bar = 10 mm.CC0 · PubMed Central
Figure 2 (A) Lung retention, cumulative fecal excretion, and lavaged fraction of 192Ir NPs with 17- to 20-nm median diameter during 6 months after a single 1- to 1.5-hr inhalation. (B) Expands the data of the first week after inhalation. Total lung retention data are the sum of measured lung and BAL fraction from each animal. All fractions are normalized to the initially deposited 192Ir NPs in the lungs. At each time point, data obtained from four rats are averaged and error bars indicate SD.
Figure 2 (A) Lung retention, cumulative fecal excretion, and lavaged fraction of 192Ir NPs with 17- to 20-nm median diameter during 6 months after a single 1- to 1.5-hr inhalation. (B) Expands the data of the first week after inhalation. Total lung retention data are the sum of measured lung and BAL fraction from each animal. All fractions are normalized to the initially deposited 192Ir NPs in the lungs. At each time point, data obtained from four rats are averaged and error bars indicate SD.CC0 · PubMed Central
Figure 3 (A,B) 192Ir NP fraction of lung deposit as determined from 192Ir radioactivity measurements in cells and supernatant after separation by centrifugation of the BAL at different time points. (B) Expands the data of the first week after inhalation. All fractions are normalized to the initially deposited 192Ir NP in the lungs. At each time point, data obtained from four rats are averaged and error bars indicate SD.
Figure 3 (A,B) 192Ir NP fraction of lung deposit as determined from 192Ir radioactivity measurements in cells and supernatant after separation by centrifugation of the BAL at different time points. (B) Expands the data of the first week after inhalation. All fractions are normalized to the initially deposited 192Ir NP in the lungs. At each time point, data obtained from four rats are averaged and error bars indicate SD.CC0 · PubMed Central
Figure 4 NPlav and estimated NP fraction retained in the NPAM together with biexponential fit: half-lives 2 and 800 days. In comparison, lavaged PSL fraction (2.1-μm polystyrene particles) in AMs are plotted together with a trend line as reported by Lehnert et al. (1989). All lavaged particle fractions are normalized to contemporary particle burden in the lungs.
Figure 4 NPlav and estimated NP fraction retained in the NPAM together with biexponential fit: half-lives 2 and 800 days. In comparison, lavaged PSL fraction (2.1-μm polystyrene particles) in AMs are plotted together with a trend line as reported by Lehnert et al. (1989). All lavaged particle fractions are normalized to contemporary particle burden in the lungs.CC0 · PubMed Central
Figure 5 Estimated fraction of translocated NP into epithelium and interstitium as NPreloc = 1−(NPfree + NPAM) with biexponential fit (half-lives 5 and 400 days) and the estimated fraction of NPfree. NPreloc, relocated fraction. For comparison, the NPAM data and the fitted curve of the AM-associated NP of Figure 4 are given. All NP fractions are normalized to contemporary particle burden in the lungs.
Figure 5 Estimated fraction of translocated NP into epithelium and interstitium as NPreloc = 1−(NPfree + NPAM) with biexponential fit (half-lives 5 and 400 days) and the estimated fraction of NPfree. NPreloc, relocated fraction. For comparison, the NPAM data and the fitted curve of the AM-associated NP of Figure 4 are given. All NP fractions are normalized to contemporary particle burden in the lungs.CC0 · PubMed Central
Figure 6 Estimated NP clearance from NP fraction retained on the epithelial surface versus observed daily fecal excretion as the result of AM-mediated NP transport from the lungs to larynx.
Figure 6 Estimated NP clearance from NP fraction retained on the epithelial surface versus observed daily fecal excretion as the result of AM-mediated NP transport from the lungs to larynx.CC0 · PubMed Central

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Research works printed but not linked: 20

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Metadata

Authors
Semmler-Behnke, M., Takenaka, S., Fertsch, S., Wenk, A., Seitz, J., Mayer, P., Oberdörster, G., & Kreyling, W. G.
Venue
Environmental Health Perspectives
Publisher
American Chemical Society (ACS)
Published
2007-02-06
Volume
115
Issue
5
Pages
728-733
ISSN
  • 0091-6765
  • 1552-9924
DOI
10.1289/ehp.9685
PMC
PMC1867986
Cited by
262
References
0
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor, 3979 d)

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