Nanoparticle translocation across mouse alveolar epithelial cell monolayers: Species-specific mechanisms

Fazlollahi, Farnoosh; Kim, Yong Ho; Sipos, Arnold; Borok, Zea; Kim, Kwang‐Jin; Crandall, Edward D.

doi:10.1016/j.nano.2013.01.007

Cited by 18 publications

(14 citation statements)

References 48 publications

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“…Consistent with this hypothesis, human studies which exposed healthy and COPD patients to inhaled nanoparticles showed that the deposition of particles increases with the severity of the disease [18], suggesting that penetration or translocation of these minute particles through the respiratory epithelium into the lung parenchyma increases when the alveolar barrier is inflamed. Consistent with those results, in vitro studies showed that a pharmacological decrease in the tight junctional resistance of mouse alveolar epithelial cell monolayers causes a drastic increase in the translocation of engineered nanoparticles across the epithelial barrier [19] and that smaller nanoparticles cross the rat alveolar epithelial monolayer 3 times faster than larger ones [20], observations which can explain the shift towards larger particles in our inflammatory models. If so, our results also predict that any inflammatory imbalance of the lung epithelial layer, regardless of its cause and magnitude, results in a similar absorption of small UFP in the lung.…”

Section: Discussionsupporting

confidence: 82%

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation

Bar-Shai

Alcalay²,

Sagiv³

et al. 2015

Respiration

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Background: Acute lung inflammation can be monitored by various biochemical readouts of bronchoalveolar lavage fluid (BALF). Objective: To analyze the BALF content of ultrafine particles (UFP; <100 nm) as an inflammatory biomarker in early diagnosis of acute and chronic lung diseases. Methods: Mice were exposed to different stress conditions and inflammatory insults (acute lipopolysaccharide inhalation, tobacco smoke and lethal dose of total body irradiation, i.e. 950 rad). After centrifugation, the cellular pellet was assessed while cytokines and ultrafine particles were measured in the soluble fraction of the BALF. Results: A characteristic UFP distribution with a D₅₀ (i.e. the dimension of the 50th UFP percentile) was shared by all tested mouse strains in the BALF of resting lungs. All tested inflammatory insults similarly shifted this size distribution, resulting in a unique UFP fingerprint with an averaged D₅₀ of 58.6 nm, compared with the mean UFP D₅₀ of 23.7 nm for resting BALF (p < 0.0001). This UFP profile was highly reproducible and independent of the intensity or duration of the inflammatory trigger. It returned to baseline after resolution of the inflammation. Neither total body irradiation nor induction of acute cough induced this fingerprint. Conclusions: The UFP fingerprint in the BALF of resting and inflamed lungs can serve as a binary biomarker of healthy and acutely inflamed lungs. This marker can be used as a novel readout for the onset of inflammatory lung diseases and for complete lung recovery from different insults.

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Section: Discussionsupporting

confidence: 82%

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation

Bar-Shai

Alcalay²,

Sagiv³

et al. 2015

Respiration

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“…Agglomerates of ENM form in biological fluids by loose binding (e.g., van der Waals force) while primary diameters, and not hydrodynamic diameters influence toxicity. In support of this, other researchers have reported that nanoparticle trafficking across lung epithelial cells was correlated with primary diameters and not the hydrodynamic diameters of the agglomerated nanoparticles [ 22 ].…”

Section: Discussionmentioning

confidence: 71%

Comparative lung toxicity of engineered nanomaterials utilizing in vitro, ex vivo and in vivo approaches

et al. 2014

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BackgroundAlthough engineered nanomaterials (ENM) are currently regulated either in the context of a new chemical, or as a new use of an existing chemical, hazard assessment is still to a large extent reliant on information from historical toxicity studies of the parent compound, and may not take into account special properties related to the small size and high surface area of ENM. While it is important to properly screen and predict the potential toxicity of ENM, there is also concern that current toxicity tests will require even heavier use of experimental animals, and reliable alternatives should be developed and validated. Here we assessed the comparative respiratory toxicity of ENM in three different methods which employed in vivo, in vitro and ex vivo toxicity testing approaches.MethodsToxicity of five ENM (SiO2 (10), CeO2 (23), CeO2 (88), TiO2 (10), and TiO2 (200); parentheses indicate average ENM diameter in nm) were tested in this study. CD-1 mice were exposed to the ENM by oropharyngeal aspiration at a dose of 100 μg. Mouse lung tissue slices and alveolar macrophages were also exposed to the ENM at concentrations of 22–132 and 3.1-100 μg/mL, respectively. Biomarkers of lung injury and inflammation were assessed at 4 and/or 24 hr post-exposure.ResultsSmall-sized ENM (SiO2 (10), CeO2 (23), but not TiO2 (10)) significantly elicited pro-inflammatory responses in mice (in vivo), suggesting that the observed toxicity in the lungs was dependent on size and chemical composition. Similarly, SiO2 (10) and/or CeO2 (23) were also more toxic in the lung tissue slices (ex vivo) and alveolar macrophages (in vitro) compared to other ENM. A similar pattern of inflammatory response (e.g., interleukin-6) was observed in both ex vivo and in vitro when a dose metric based on cell surface area (μg/cm2), but not culture medium volume (μg/mL) was employed.ConclusionExposure to ENM induced acute lung inflammatory effects in a size- and chemical composition-dependent manner. The cell culture and lung slice techniques provided similar profiles of effect and help bridge the gap in our understanding of in vivo, ex vivo, and in vitro toxicity outcomes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-014-0047-3) contains supplementary material, which is available to authorized users.

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“…Besides secretion of surfactant, ATII cells have also been shown to sense invading pathogens to produce antimicrobial products and amplify the inflammatory response by secretion of cytokine and chemokines [61,62]. Particularly for nanoparticles, the alveolar epithelial layer has been described to accomplish uptake and translocation of deposited materials [63,64]. For agglomerated carbonaceous particles this process might however be not effective enough [65] to a detection of epithelial internalized CNP agglomerates by light microscopy (Fig.…”

Section: Discussionmentioning

confidence: 99%

No involvement of alveolar macrophages in the initiation of carbon nanoparticle induced acute lung inflammation in mice

et al. 2015

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BackgroundCarbonaceous nanoparticles (CNP) represent a major constituent of urban particulate air pollution, and inhalation of high CNP levels has been described to trigger a pro-inflammatory response of the lung. While several studies identified specific particle characteristics driving respiratory toxicity of low-solubility and low-toxicity particles such as CNP, the major lung cell type, which initiates and drives that response, remains still uncertain. Since alveolar macrophages (AM) are known to effectively phagocytose inhaled particles and play a crucial role for the initiation of pulmonary inflammation caused by invading microbes, we aimed to determine their role for sterile stimuli such as CNP by profiling the primary alveolar cell compartments of the lung. We exposed C57BL/6 mice to 20 μg CNP by intratracheal instillation and comprehensively investigated the expression of the underlying mediators during a time span of 3 to 72 h in three different lung cell populations: CD45- (negative) structural cells, CD45+ (positive) leukocytes, and by BAL recovered cells.ResultsBronchoalveolar lavage (BAL) analysis revealed an acute inflammatory response characterized by the most prominent culmination of neutrophil granulocytes from 12 to 24 h after instillation, which declined to basal levels by day 7. As early as 3 h after CNP exposure 50 % of the AM revealed particle laden. BAL concentrations and lung gene expression profiles of TNFα, and the neutrophil chemoattractants CXCL1,-2 and-5 preceded the neutrophil recruitment and showed highest levels after 12 h of CNP exposure, pointing to a significant activation of the inflammation-evoking lung cells at this point of time. AM, isolated from lungs 3 to 12 h after CNP instillation, however, did not show a pro-inflammatory signature. On the contrary, gene expression analysis of different lung cell populations isolated 12 h after CNP instillation revealed CD45-, mainly representing alveolar epithelial type II (ATII) cells as major producer of inflammatory CXCL cytokines. Particularly by CD45- cells expressed Cxcl5 proved to be the most abundant chemokine, being 12 h after CNP exposure 24 (±11) fold induced.ConclusionOur data suggests that AM are noninvolved in the initiation of the inflammatory response. ATII cells, which induced highest CXCL levels early on, might in contrast be the driver of acute neutrophilic inflammation upon pulmonary CNP exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0144-6) contains supplementary material, which is available to authorized users.

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Nanoparticle translocation across mouse alveolar epithelial cell monolayers: Species-specific mechanisms

Cited by 18 publications

References 48 publications

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation

Fingerprint of Lung Fluid Ultrafine Particles, a Novel Marker of Acute Lung Inflammation

Comparative lung toxicity of engineered nanomaterials utilizing in vitro, ex vivo and in vivo approaches

No involvement of alveolar macrophages in the initiation of carbon nanoparticle induced acute lung inflammation in mice

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