Asian dust particles induce macrophage inflammatory responses via mitogen-activated protein kinase activation and reactive oxygen species production.

Asian dust is a springtime meteorological phenomenon that originates in the deserts of China and Mongolia. The dust is carried by prevailing winds across East Asia where it causes serious health problems. Most of the information available on the impact of Asian dust on human health is based on epidemiological investigations, so from a biological standpoint little is known of its effects. To clarify the effects of Asian dust on human health, it is essential to assess inflammatory responses to the dust and to evaluate the involvement of these responses in the pathogenesis or aggravation of disease. Here, we investigated the induction of inflammatory responses by Asian dust particles in macrophages. Treatment with Asian dust particles induced greater production of inflammatory cytokines interleukin-6 and tumor necrosis factor- α (TNF- α ) compared with treatment with soil dust. Furthermore, a soil dust sample containing only particles ≤10 µ m in diameter provoked a greater inflammatory response than soil dust samples containing particles >10 µ m. In addition, Asian dust particles-induced TNF- α production was dependent on endocytosis, the production of reactive oxygen species, and the activation of nuclear factor- κ B and mitogen-activated protein kinases. Together, these results suggest that Asian dust particles induce inflammatory disease through the activation of macrophages.

Promotion of allergic immune responses by intranasally-administrated nanosilica particles in mice.

With the increase in use of nanomaterials, there is growing concern regarding their potential health risks. However, few studies have assessed the role of the different physical characteristics of nanomaterials in allergic responses. Here, we examined whether intranasally administered silica particles of various sizes have the capacity to promote allergic immune responses in mice. We used nanosilica particles with diameters of 30 or 70 nm (nSP30 or nSP70, respectively), and conventional micro-sized silica particles with diameters of 300 or 1000 nm (nSP300 or mSP1000, respectively). Mice were intranasally exposed to ovalbumin (OVA) plus each silica particle, and the levels of OVA-specific antibodies (Abs) in the plasma were determined. Intranasal exposure to OVA plus smaller nanosilica particles tended to induce a higher level of OVA-specific immunoglobulin (Ig) E, IgG and IgG1 Abs than did exposure to OVA plus larger silica particles. Splenocytes from mice exposed to OVA plus nSP30 secreted higher levels of Th2-type cytokines than mice exposed to OVA alone. Taken together, these results indicate that nanosilica particles can induce allergen-specific Th2-type allergic immune responses in vivo. This study provides the foundations for the establishment of safe and effective forms of nanosilica particles.

Acute phase proteins as biomarkers for predicting the exposure and toxicity of nanomaterials.

Recently, nanomaterials have become an integral part of our daily lives. However, there is increasing concern about the potential risk to human health. Here, we attempted to identify biomarkers for predicting the exposure and toxicity of nanomaterials by using a proteomics based approach. We evaluated the changes of protein expression in plasma after treatment with silica nanoparticles. Our analyses identified haptoglobin, one of the acute phase proteins, as a candidate biomarker. The results of ELISA showed that the level of haptoglobin was significantly elevated in plasma of mice exposed to silica nanoparticles with a diameter of 70 nm (nSP70) compared to normal mice and those exposed to silica particles with a diameter of 1000 nm. Furthermore, the other acute phase proteins, C-reactive protein (CRP) and serum amyloid A (SAA) were also elevated in plasma of nSP70 treated mice. In addition, the level of these acute phase proteins was elevated in the plasma of mice after intranasal treatment with nSP30. Our results suggest that haptoglobin, CRP and SAA are highly sensitive biomarkers for assessing the risk of exposure to silica nanoparticles. We believe this study will contribute to the development of global risk assessment techniques for nanomaterials.

Potential adjuvant effect of intranasal urban aerosols in mice through induction of dendritic cell maturation.

Urban air pollution is a crucial environmental problem in industrialized and developing countries. Although epidemiologic studies have associated exposure to urban aerosols with exacerbations of allergic airway diseases, the underlying mechanism of toxicity is largely unknown. Here, we evaluated the effect of urban aerosols from China, on the induction of allergic diseases in vivo and on the function of dendritic cells (DCs) in vitro. Mice were intranasally given urban aerosol plus ovalbumin (OVA), and the levels of OVA-specific antibodies in the plasma were determined. Urban aerosol induced higher OVA-specific immunoglobulin (Ig) G and IgE responses than OVA alone. Furthermore, urban aerosol plus OVA induced high levels of histamine production, indicating that exposure to the aerosol could cause serious allergic symptoms. Next, we examined the effect of urban aerosol on DCs. The aerosol enhanced cell-surface expression of co-stimulatory molecules such as CD80 and CD86 and the production of interleukin (IL)-1ß and IL-6 on DCs. In addition, allogeneic T-cell-stimulation assay showed that the urban aerosol could activate T cells through maturation of DCs. These results indicate that urban aerosols can induce allergic airway diseases through activation of DCs.

Urban aerosols induce pro-inflammatory cytokine production in macrophages and cause airway inflammation in vivo.

Urban air pollution, especially in developing countries, is a crucial environmental problem. Urban aerosols may contain various kinds of substances and induce harmful effects such as allergic diseases. Therefore, it is critical to clarify the biological effects of urban aerosols on human health. In this study, we evaluated the induction of airway inflammation in vitro and in vivo due to exposure of urban aerosols. We investigated cytokine production and nuclear factor-kappaB (NF-kappaB) activation after stimulation of macrophage cells by exposure of urban aerosols. Urban aerosols were found to induce the production of interleukin (IL)-8, tumor necrosis factor-alpha and IL-1beta on macrophage cells. In addition, we showed that NF-kappaB pathway regulated the urban aerosols-induced inflammatory cytokine response. Moreover, the intranasal administration of urban aerosols resulted in increases in the total cell number in bronchoalveolar lavage and infiltration of eosinophils in lung tissue. These results indicate that urban aerosols induce respiratory inflammation and onset of inflammatory disease due to an activation of the immune system.

Carbon nanotubes elicit DNA damage and inflammatory response relative to their size and shape.

Carbon nanotubes (CNTs) have been one of the most extensively researched and developed nanomaterials. However, little concern has been placed on their safety. The biological effects of CNTs are believed to differ relative to size and shape. Thus, the relationship between the characteristics of CNTs and their safety needs to be evaluated. In this study, we examined the biological effects of different-sized multi-walled CNTs (MWCNTs) and single-walled CNTs (SWCNTs). Long and thick MWCNTs induced the strongest DNA damage while similar SWCNTs caused little effect. Comparison of inflammatory responses of various types of CNTs found that peritoneal CNT administration of long and thick MWCNTs increased the total cell number in abdominal lavage fluid in mice. These results indicate that long and thick MWCNT, but not short and thin MWCNT, cause DNA damage and severe inflammatory effects. These findings might provide useful information for constructing novel CNTs with safety.

Metabolic impact of overexpression of liver glycogen synthase with serine-to-alanine substitutions in rat primary hepatocytes.

To investigate the effect of elevation of liver glycogen synthase (GYS2) activity on glucose and glycogen metabolism, we performed adenoviral overexpression of the mutant GYS2 with six serine-to-alanine substitutions in rat primary hepatocytes. Cell-free assays demonstrated that the serine-to-alanine substitutions caused constitutive activity and electrophoretic mobility shift. In rat primary hepatocytes, overexpression of the mutant GYS2 significantly reduced glucose production by 40% and dramatically induced glycogen synthesis via the indirect pathway rather than the direct pathway. Thus, we conclude that elevation of glycogen synthase activity has an inhibitory effect on glucose production in hepatocytes by shunting gluconeogenic precursors into glycogen. In addition, although intracellular compartmentation of glucose-6-phosphate (G6P) remains unclear in hepatocytes, our results imply that there are at least two G6P pools via gluconeogenesis and due to glucose phosphorylation, and that G6P via gluconeogenesis is preferentially used for glycogen synthesis in hepatocytes.