Assessment of Cytokine-Induced Neutrophil Chemoattractants as Biomarkers for Prediction of Pulmonary Toxicity of Nanomaterials.

Takako Oyabu,Shingo Noguchi,Manabu Shimada,Byeong-Woo Lee,Masaru Kubo,Kazuhiro Yatera,Taisuke Tomonaga,Chinatsu Nishida,Yasuo Morimoto,Hiroto Izumi

doi:10.3390/nano10081563

Abstract

This work determines whether cytokine-induced neutrophil chemoattractants (CINC)-1, CINC-2 and CINC-3 can be markers for predicting high or low pulmonary toxicity of nanomaterials (NMs). We classified NMs of nickel oxide (NiO) and cerium dioxide (CeO2) into high toxicity and NMs of two types of titanium dioxides (TiO2 (P90 and rutile)) and zinc oxide (ZnO) into low toxicity, and we analyzed previous data of CINCs in bronchoalveolar lavage fluid (BALF) of rats from three days to six months after intratracheal instillation (0.2 and 1.0 mg) and inhalation exposure (0.32–10.4 mg/m3) of materials (NiO, CeO2, TiO2 (P90 and rutile), ZnO NMs and micron-particles of crystalline silica (SiO2)). The concentration of CINC-1 and CINC-2 in BALF had different increase tendency between high and low pulmonary toxicity of NMs and correlated with the other inflammatory markers in BALF. However, CINC-3 increased only slightly in a dose-dependent manner compared with CINC-1 and CINC-2. Analysis of receiver operating characteristics for the toxicity of NMs by CINC-1 and CINC-2 showed the most accuracy of discrimination of the toxicity at one week or one month after exposure and CINC-1 and CINC-2 in BALF following intratracheal instillation of SiO2 as a high toxicity could accurately predict the toxicity at more than one month after exposure. These data suggest that CINC-1 and CINC-2 may be useful biomarkers for the prediction of pulmonary toxicity of NMs relatively early in both intratracheal instillation and inhalation exposure.

Highlights

In recent years, materials with physicochemical properties of peculiar to nanoparticles have been used in various industrial fields, such as photocatalysts, cosmetics, sunscreens, solar panels and semiconductors
We examined the usefulness of cytokine-induced neutrophil chemoattractants (CINC)-3 to evaluate pulmonary toxicity using bronchoalveolar lavage fluid (BALF) obtained by intratracheal instillation of nickel oxide (NiO) and TiO2 (P90)
In intratracheal instillation studies of nickel oxide nanoparticles with different aggregate diameters, persistent increases of CINC-3 were observed in severe inflammation caused by a high dose (1.0 mg), and there was no increase in the mild inflammation caused by a low dose (0.2 mg) [18,50]

Summary

Introduction

Materials with physicochemical properties of peculiar to nanoparticles have been used in various industrial fields, such as photocatalysts, cosmetics, sunscreens, solar panels and semiconductors. It has been reported that nanoparticles generally cause greater pulmonary inflammation than micrometer-sized particles, raising concern about their harmful respiratory effects on workers handling nanomaterials (NMs), due to inhalation via the airway. An important aspect of the pulmonary toxicity of NMs is that it involves lung inflammation, and irreversible pathologic conditions such as fibrosis and tumors in the chronic phase. Inhaled chemicals penetrate into the pulmonary alveolar space and cytokines are released from macrophages and injured lung tissue. These cytokines, especially chemokines, promote the migration and activation of neutrophils, which is how inflammation, mainly by neutrophils, progresses. Inflammation causes irreversible lesions, fibrosis and tumors [1,2,3]. Silica and asbestos, which are known to cause lung tumors and fibrosis, have been observed to cause persistent inflammation [4,5,6], while it has been reported that low-toxicity titanium dioxide and fullerenes induced transient inflammation [7,8]

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