Involvement of macrophage inflammatory protein 1α (MIP1α) in promotion of rat lung and mammary carcinogenic activity of nanoscale titanium dioxide particles administered by intra-pulmonary spraying

Xu, Jiegou; Futakuchi, Mitsuru; Iigo, Masaaki; Fukamachi, Katsumi; Alexander, David B.; Shimizu, Hideo; Sakai, Yuto; Tamano, Seiko; Furukawa, Fumio; Uchino, Tadashi; Tokunaga, Hiroshi; Nishimura, Takuya; Hirose, Akihiko; Kanno, Jun; Tsuda, Hiroyuki

doi:10.1093/carcin/bgq029

Cited by 49 publications

(36 citation statements)

References 44 publications

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“…Intrapulmonary spraying has been shown to be an efficient method to deliver particle materials deep into the lung. (20)(21)(22)(23)(24) Our results demonstrated that MWCNT, like asbestos, translocated from the lung into the pleural cavity and induced inflammatory responses in the pleural cavity and, importantly, hyperplastic visceral mesothelial proliferation. These findings are important in understanding whether MWCNT have the potential to cause asbestos-like pleural lesions.…”

mentioning

confidence: 64%

“…(38) Previously, we used a total dose of 1.25 mg/rat of titanium dioxide over a 9-day period and identified factors involved in titanium dioxide-induced lung lesions. (24) In the present study, we used the same protocol for the purpose of induction of observable pleural lesions and inflammation in the pleural cavity as well to ensure the presence of a detectable number of fibers in the pleural cavity after short-term administration; this dose was higher than the NIOSH exposure limit. Time-and dose-dependent experiments are needed in future studies, and further investigation is also required to elucidate cytokines and other factors that cause parietal mesothelial proliferation in animal models that are more relevant to humans.…”

Section: Discussionmentioning

confidence: 99%

“…We used the intrapulmonary spraying technique that was developed in our laboratory. (24) Briefly, rats were anaesthetized using isoflurane; the mouth was fully opened with the tongue gently held and the nozzle of a microsprayer (series IA-1B Intratracheal Aerosolizer; Penn-century, Philadelphia, PA, USA) was inserted into the trachea through the larynx and 0.5 mL suspension was sprayed into the lungs synchronizing with spontaneous respiratory inhalation. We confirmed that the dosed materials were distributed deep into the lung tissue and reached most of the terminal alveoli without causing obvious respiratory distress.…”

Section: Methodsmentioning

confidence: 99%

“…The induction and preparation of primary alveolar macrophages (PAM) has been described previously. (24) PAM were seeded into 6 cm culture dishes at 2 9 10 6 cells per well in 10% FBS RPMI 1640. After overnight incubation, the culture media was refreshed and MWCNT-N, MWCNT-M or CRO suspensions were added to the cells to a final concentration of 10 lg/mL.…”

Section: Methodsmentioning

confidence: 99%

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Multi‐walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats

et al. 2012

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Multi-walled carbon nanotubes have a fibrous structure similar to asbestos and induce mesothelioma when injected into the peritoneal cavity. In the present study, we investigated whether carbon nanotubes administered into the lung through the trachea induce mesothelial lesions. Male F344 rats were treated with 0.5 mL of 500 lg/mL suspensions of multi-walled carbon nanotubes or crocidolite five times over a 9-day period by intrapulmonary spraying. Pleural cavity lavage fluid, lung and chest wall were then collected. Multi-walled carbon nanotubes and crocidolite were found mainly in alveolar macrophages and mediastinal lymph nodes. Importantly, the fibers were also found in the cell pellets of the pleural cavity lavage, mostly in macrophages. Both multi-walled carbon nanotube and crocidolite treatment induced hyperplastic proliferative lesions of the visceral mesothelium, with their proliferating cell nuclear antigen indices approximately 10-fold that of the vehicle control. The hyperplastic lesions were associated with inflammatory cell infiltration and inflammationinduced fibrotic lesions of the pleural tissues. The fibers were not found in the mesothelial proliferative lesions themselves. In the pleural cavity, abundant inflammatory cell infiltration, mainly composed of macrophages, was observed. Conditioned cell culture media of macrophages treated with multi-walled carbon nanotubes and crocidolite and the supernatants of pleural cavity lavage fluid from the dosed rats increased mesothelial cell proliferation in vitro, suggesting that mesothelial proliferative lesions were induced by inflammatory events in the lung and pleural cavity and likely mediated by macrophages. In conclusion, intrapulmonary administration of multi-walled carbon nanotubes, like asbestos, induced mesothelial proliferation potentially associated with mesothelioma development. (Cancer Sci 2012; 103: 2045-2050 M ulti-walled carbon nanotubes (MWCNT) are structurally composed of cylinders rolled up from several layers of graphite sheets. They are several to tens of nanometers in diameter and several to tens of micrometers in length. This high length to diameter aspect ratio, a characteristic shared with asbestos fibers, has led to concern that exposure to MWCNT might cause asbestos-like lung diseases, such as lung fibrosis, lung cancer, pleural plaque and malignant mesothelioma.(1-6) Pleural plaque and malignant mesothelioma are characteristic lesions in asbestos-exposed humans. Although fiber dimensions, biopersistence, oxidative stress and inflammation have all been implicated, (7)(8)(9)(10)(11)(12) the exact mechanisms of pleural pathogenesis are unclear. According to a pathogenesis paradigm suggested by Donaldson et al.,asbestos fibers penetrate into the pleural cavity from the alveoli and deposit in the pleural tissue. Unlike spherical particles, fibrous materials such as asbestos are not cleared effectively from the pleural cavity, resulting in deposition of the fibers in the parietal pleura. This deposition, in turn, causes frustrated ...

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confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Multi‐walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats

et al. 2012

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“…Studies have also shown that carbon black nanoparticles (9)(10)(11), titanium dioxide nanoparticles (12), and carbon nanotubes (13,14) can promote allergic sensitization, allergic airway inflammation (AAI), and/or stimulate dendritic cell (DC) and allergen-specific T cells. However, a significant component of these particle adjuvant effects has been attributed to adsorbed toxic chemicals and metallic impurities and the ability to induce oxidative stress (6,7,13,(15)(16)(17)(18)(19). Notably, information regarding the long-term effects of inert, nontoxic and noninflammatory nanoparticles delivered into the lung on asthma development and pulmonary DC distribution and function is lacking.…”

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confidence: 99%

Inert 50-nm Polystyrene Nanoparticles That Modify Pulmonary Dendritic Cell Function and Inhibit Allergic Airway Inflammation

Hardy

Lemasurier

Belz

et al. 2012

The Journal of Immunology

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Nanoparticles are being developed for diverse biomedical applications, but there is concern about their potential to promote inflammation, particularly in the lung. Although a variety of ambient, anthropogenic and man-made nanoparticles can promote lung inflammation, little is known about the long-term immunomodulatory effects of inert noninflammatory nanoparticles. We previously showed polystyrene 50-nm nanoparticles coated with the neutral amino acid glycine (PS50G nanoparticles) are not inflammatory and are taken up preferentially by dendritic cells (DCs) in the periphery. We tested the effects of such nanoparticles on pulmonary DC function and the development of acute allergic airway inflammation. Surprisingly, exposure to PS50G nanoparticles did not exacerbate but instead inhibited key features of allergic airway inflammation including lung airway and parenchymal inflammation, airway epithelial mucus production, and serum allergen-specific IgE and allergen-specific Th2 cytokines in the lung-draining lymph node (LN) after allergen challenge 1 mo later. PS50G nanoparticles themselves did not induce lung oxidative stress or cardiac or lung inflammation. Mechanistically, PS50G nanoparticles did not impair peripheral allergen sensitization but exerted their effect at the lung allergen challenge phase by inhibiting expansion of CD11c+MHCIIhi DCs in the lung and draining LN and allergen-laden CD11bhiMHCIIhi DCs in the lung after allergen challenge. PS50G nanoparticles further suppressed the ability of CD11bhi DCs in the draining LN of allergen-challenged mice to induce proliferation of OVA-specific CD4+ T cells. The discovery that a defined type of nanoparticle can inhibit, rather than promote, lung inflammation via modulation of DC function opens the door to the discovery of other nanoparticle types with exciting beneficial properties.

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Titandioxid (alveolengängige Fraktion) [MAK Value Documentation in German language, 2019]

Hartwig

Arand²

2019

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated titanium dioxide [ 13463‐67‐1 ]. Titanium dioxide causes lung tumours in rats at high concentrations. In 2009, titanium dioxide was evaluated and, because a maximum concentration at the workplace (MAK value) could not be established, it was classified in Carcinogen Category 3A. Titanium dioxide is a biopersistent granular dust and, in a later evaluation, inhalation studies with titanium dioxide were used to derive the general threshold limit value for granular biopersistent dusts. Therefore, the respirable fraction of titanium dioxide dust is reclassified in Carcinogen Category 4 and a MAK value of 0.3 mg/m 3 × material density is established for the respirable fraction according to the general threshold value for biopersistent granular dusts. Reclassification in Carcinogen Category 4 is justified because the lung tumours are regarded as a consequence of the inflammatory mechanism of action, for which a threshold can be defined. Direct genotoxic effects appear to be of subordinate relevance for the carcinogenicity of biopersistent granular dusts. By analogy with the biopersistent granular dusts, Peak Limitation Category II is established for titanium dioxide with an excursion factor of 8. Since titanium dioxide is not systemically distributed and accumulates only locally in the lungs, damage to the embryo or foetus is unlikely when the MAK value is not exceeded. Titanium dioxide is classified accordingly in Pregnancy Risk Group C. Titanium dioxide is not expected to be a sensitizer and is not taken up via the skin in toxicologically relevant amounts.

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Involvement of macrophage inflammatory protein 1α (MIP1α) in promotion of rat lung and mammary carcinogenic activity of nanoscale titanium dioxide particles administered by intra-pulmonary spraying

Cited by 49 publications

References 44 publications

Multi‐walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats

Multi‐walled carbon nanotubes translocate into the pleural cavity and induce visceral mesothelial proliferation in rats

Inert 50-nm Polystyrene Nanoparticles That Modify Pulmonary Dendritic Cell Function and Inhibit Allergic Airway Inflammation

Titandioxid (alveolengängige Fraktion) [MAK Value Documentation in German language, 2019]

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