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Intratracheal instillation of single-wall carbon nanotubes in the rat lung induces time-dependent changes in gene expression.

Fujita K, Fukuda M, Fukui H, Horie M, Endoh S, Uchida K, Shichiri M, Morimoto Y, Ogami A, Iwahashi H - Nanotoxicology (2014)

Bottom Line: In addition, the expression levels of Atp6v0d2, Lpo, Mmp7, Mmp12 and Rnase9 were significantly upregulated until 754 days post-instillation.We propose that these persistently upregulated genes in the chronic-phase response following the acute-phase response act as potential biomarkers in lung tissue after SWCNT instillation.This study provides further insight into the time-dependent changes in genomic expression associated with the pulmonary toxicity of SWCNTs.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan .

ABSTRACT
The use of carbon nanotubes in the industry has grown; however, little is known about their toxicological mechanism of action. Single-wall carbon nanotube (SWCNT) suspensions were administered by single intratracheal instillation in rats. Persistence of alveolar macrophage-containing granuloma was observed around the sites of SWCNT aggregation at 90 days post-instillation in 0.2-mg- or 0.4-mg-injected doses per rat. Meanwhile, gene expression profiling revealed that a large number of genes involved in the inflammatory response were markedly upregulated until 90 days or 180 days post-instillation. Subsequently, gene expression patterns were dramatically altered at 365 days post-instillation, and the number of upregulated genes involved in the inflammatory response was reduced. These results suggested that alveolar macrophage-containing granuloma reflected a characteristic of the histopathological transition period from the acute-phase to the subchronic-phase of inflammation, as well as pulmonary acute phase response persistence up to 90 or 180 days after intratracheal instillation in this experimental setting. The expression levels of the genes Ctsk, Gcgr, Gpnmb, Lilrb4, Marco, Mreg, Mt3, Padi1, Slc26a4, Spp1, Tnfsf4 and Trem2 were persistently upregulated in a dose-dependent manner until 365 days post-instillation. In addition, the expression levels of Atp6v0d2, Lpo, Mmp7, Mmp12 and Rnase9 were significantly upregulated until 754 days post-instillation. We propose that these persistently upregulated genes in the chronic-phase response following the acute-phase response act as potential biomarkers in lung tissue after SWCNT instillation. This study provides further insight into the time-dependent changes in genomic expression associated with the pulmonary toxicity of SWCNTs.

No MeSH data available.


Related in: MedlinePlus

Time-dependent changes in p values of statistically over-represented GO terms of H-SWCNT-induced genes.
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Figure 0005: Time-dependent changes in p values of statistically over-represented GO terms of H-SWCNT-induced genes.

Mentions: The SWCNT aggregates (black patches) were observed around bronchi or bronchioles in dissected lungs in both of the SWCNT groups during the observation period, while no obvious morphological changes were observed in the vehicle control group. The appearance of the SWCNT aggregates resulted in a time-dependent decrease in each group (Figure 2). Histopathological findings of lungs stained with hematoxylin and eosin showed that fine granular substances, which were phagocytosed by persistent alveolar macrophages, were observed in the alveoli, alveolar wall and bronchioles in both SWCNT groups during the observation period (Table 1 and Figure 3). Persistence of macrophages laden with SWCNT aggregates as granular substances was observed in the alveolar walls and alveoli at three days post-instillation in both SWCNT groups (Figure 3B1 and C1), at seven days post-instillation in both SWCNTs groups (Figure 3B2 and C2) and at 30 days post-instillation in the L-SWCNT group (Figure 3B3). However, inflammatory cell infiltration was barely discerned in each of the experimental groups. A pale-pink fibrin deposition was observed in pulmonary alveoli at 30 days post-instillation in the H-SWCNT group (Figure 3C3). Persistence of macrophages laden with SWCNT aggregates as granular substances was observed in the alveolar walls and alveoli at 90 days post-instillation in the L-SWCNT group (Figure 3B4). The proliferation of collagen fibers in the persistent alveolar macrophage-containing granuloma around the sites of SWCNT aggregates was observed at 90 days post-instillation in the H-SWCNT group (Figure 3C4). Macrophage-containing granuloma or foamy alveolar macrophage-containing granuloma around the sites of SWCNT aggregates was observed at 180 days post-instillation in the L-SWCNT or H-SWCNT group, respectively (Figure 3B5 and C5). Persistent macrophage-containing SWCNT aggregates as granular substances were diffusely localized in the alveolar walls and alveoli at 365 or 754 days post-instillation in both SWCNT groups (Figure 3B6, C6, B7 and C7). Masson's trichrome staining confirmed the absence of fibrotic lesions in each of the experimental groups (Supplementary Figure 1).Figure 2.


Intratracheal instillation of single-wall carbon nanotubes in the rat lung induces time-dependent changes in gene expression.

Fujita K, Fukuda M, Fukui H, Horie M, Endoh S, Uchida K, Shichiri M, Morimoto Y, Ogami A, Iwahashi H - Nanotoxicology (2014)

Time-dependent changes in p values of statistically over-represented GO terms of H-SWCNT-induced genes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4487535&req=5

Figure 0005: Time-dependent changes in p values of statistically over-represented GO terms of H-SWCNT-induced genes.
Mentions: The SWCNT aggregates (black patches) were observed around bronchi or bronchioles in dissected lungs in both of the SWCNT groups during the observation period, while no obvious morphological changes were observed in the vehicle control group. The appearance of the SWCNT aggregates resulted in a time-dependent decrease in each group (Figure 2). Histopathological findings of lungs stained with hematoxylin and eosin showed that fine granular substances, which were phagocytosed by persistent alveolar macrophages, were observed in the alveoli, alveolar wall and bronchioles in both SWCNT groups during the observation period (Table 1 and Figure 3). Persistence of macrophages laden with SWCNT aggregates as granular substances was observed in the alveolar walls and alveoli at three days post-instillation in both SWCNT groups (Figure 3B1 and C1), at seven days post-instillation in both SWCNTs groups (Figure 3B2 and C2) and at 30 days post-instillation in the L-SWCNT group (Figure 3B3). However, inflammatory cell infiltration was barely discerned in each of the experimental groups. A pale-pink fibrin deposition was observed in pulmonary alveoli at 30 days post-instillation in the H-SWCNT group (Figure 3C3). Persistence of macrophages laden with SWCNT aggregates as granular substances was observed in the alveolar walls and alveoli at 90 days post-instillation in the L-SWCNT group (Figure 3B4). The proliferation of collagen fibers in the persistent alveolar macrophage-containing granuloma around the sites of SWCNT aggregates was observed at 90 days post-instillation in the H-SWCNT group (Figure 3C4). Macrophage-containing granuloma or foamy alveolar macrophage-containing granuloma around the sites of SWCNT aggregates was observed at 180 days post-instillation in the L-SWCNT or H-SWCNT group, respectively (Figure 3B5 and C5). Persistent macrophage-containing SWCNT aggregates as granular substances were diffusely localized in the alveolar walls and alveoli at 365 or 754 days post-instillation in both SWCNT groups (Figure 3B6, C6, B7 and C7). Masson's trichrome staining confirmed the absence of fibrotic lesions in each of the experimental groups (Supplementary Figure 1).Figure 2.

Bottom Line: In addition, the expression levels of Atp6v0d2, Lpo, Mmp7, Mmp12 and Rnase9 were significantly upregulated until 754 days post-instillation.We propose that these persistently upregulated genes in the chronic-phase response following the acute-phase response act as potential biomarkers in lung tissue after SWCNT instillation.This study provides further insight into the time-dependent changes in genomic expression associated with the pulmonary toxicity of SWCNTs.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology (AIST) , Tsukuba , Japan .

ABSTRACT
The use of carbon nanotubes in the industry has grown; however, little is known about their toxicological mechanism of action. Single-wall carbon nanotube (SWCNT) suspensions were administered by single intratracheal instillation in rats. Persistence of alveolar macrophage-containing granuloma was observed around the sites of SWCNT aggregation at 90 days post-instillation in 0.2-mg- or 0.4-mg-injected doses per rat. Meanwhile, gene expression profiling revealed that a large number of genes involved in the inflammatory response were markedly upregulated until 90 days or 180 days post-instillation. Subsequently, gene expression patterns were dramatically altered at 365 days post-instillation, and the number of upregulated genes involved in the inflammatory response was reduced. These results suggested that alveolar macrophage-containing granuloma reflected a characteristic of the histopathological transition period from the acute-phase to the subchronic-phase of inflammation, as well as pulmonary acute phase response persistence up to 90 or 180 days after intratracheal instillation in this experimental setting. The expression levels of the genes Ctsk, Gcgr, Gpnmb, Lilrb4, Marco, Mreg, Mt3, Padi1, Slc26a4, Spp1, Tnfsf4 and Trem2 were persistently upregulated in a dose-dependent manner until 365 days post-instillation. In addition, the expression levels of Atp6v0d2, Lpo, Mmp7, Mmp12 and Rnase9 were significantly upregulated until 754 days post-instillation. We propose that these persistently upregulated genes in the chronic-phase response following the acute-phase response act as potential biomarkers in lung tissue after SWCNT instillation. This study provides further insight into the time-dependent changes in genomic expression associated with the pulmonary toxicity of SWCNTs.

No MeSH data available.


Related in: MedlinePlus