Effects of inhalation of multi-walled carbon nanotube (MWCNT) on respiratory syncytial virus (RSV) infection in mice.

Multi-walled carbon nanotubes (MWCNTs), a kind of nanomaterial, are widely used in battery electrodes and composite materials, but the adverse effects associated with their accumulation in the living body have not been sufficiently investigated. MWCNTs are a fibrous material with molecules similar to asbestos fibers, and there are concerns about its effects on the respiratory system. In this study, we conducted a risk assessment by exposing mice using a previously developed nanomaterial inhalation exposure method. We quantified the exposure in the lungs by a lung burden test, evaluated the deterioration due to pneumonia using respiratory syncytial virus (RSV) infection, and measured inflammatory cytokines in bronchoalveolar lavage fluid (BALF). As a result, in the lung burden test, the amount of MWCNT in the lung increased according to the inhalation dose. In the RSV infection experiment, CCL3, CCL5, and TGF-ß, which are indicators of inflammation and lung fibrosis, were elevated in the MWCNT-exposed group. Histological examination revealed cells phagocytosing MWCNT fibers. These phagocytic cells were also seen during the recovery period from RSV infection. The present study found that MWCNT remained in the lungs for about a month or more, suggesting that the fibers may continue to exert immunological effects on the respiratory system. Furthermore, the inhalation exposure method enabled the exposure of nanomaterials to the entire lung lobe, allowing a more detailed evaluation of the effects on the respiratory system.

Effect of inactivated Streptococcus pneumoniae as non-pathogenic particles on the severity of pneumonia caused by respiratory syncytial virus infection in mice.

The severity of pneumonia in respiratory syncytial virus (RSV) infection is strongly related to host immune response and external factors such as bacteria and environmental chemicals. We investigated the effect of inactivated Streptococcus pneumoniae (ISP) as non-pathogenic particles on the severity of pneumonia in RSV-infected mice. Mice were intranasally exposed to ISP before RSV infection. On day 5 post-infection, we examined tissues, virus titer, and infiltrated cells in the lungs. The ISP did not cause significant histopathological effects in the lungs of RSV infected mice, but reduced virus titer. It also reduced the ratio of lymphocyte infiltration into the lungs and consequently the ratio of macrophage increased. In addition, we found that ISP increased RANTES level in bronchoalveolar lavage fluid from RSV-infected mice on day 1 post-infection, but reduced type I interferon levels. Thus, ISP did not exacerbate pneumonia in RSV infection, rather, it might mildly reduce the severity. We characterize and discuss the inherent activity of ISP as non-pathogenic particles inducing the role of RANTES on the pneumonia in RSV infection.

Perinatal exposure to tetrabromobisphenol A (TBBPA), a brominated flame retardant, exacerbated the pneumonia in respiratory syncytial virus (RSV)-infected offspring mice.

To investigate the effects of perinatal exposure to tetrabromobisphenol A (TBBPA), a brominated flame retardant, on the immune system, a respiratory syncytial virus (RSV) infection mouse model was utilized. Female mice were exposed to TBBPA mixed with the diet from 10 days after conception to weaning on postnatal day 21. Offspring mice were infected intranasally with A2 strain of RSV. Although no general toxicological sign was observed, the pulmonary viral titers of offspring mice exposed to 0.1% TBBPA were significantly increased compared with the control on day 5 post-infection. TBBPA did not affect RSV growth in vitro. Histopathological analysis confirmed that the exacerbation of interstitial pneumonia was due to TBBPA- exposure in the lung tissues in RSV-infected offspring. Moreover, gene expression of interleukin (IL)-24 was shown to be elevated typically in the lung tissues of TBBPA-treated offspring by a DNA microarray and was also confirmed by immunohistopathological analysis using an anti-IL-24 antibody. Thus, developmental exposure to TBBPA affected the immune response to RSV infection, resulting in the exacerbation of pneumonia. Thus, IL-24 should be a key molecule to understand the mechanism of action of TBBPA.

Titanium dioxide nanoparticles exacerbate pneumonia in respiratory syncytial virus (RSV)-infected mice.

To reveal the effects of TiO2 nanoparticles, used in cosmetics and building materials, on the immune response, a respiratory syncytial virus (RSV) infection mouse model was used. BALB/c mice were exposed once intranasally to TiO2 at 0.5mg/kg and infected intranasally with RSV five days later. The levels of IFN-γ and chemokine CCL5, representative markers of pneumonia, in the bronchoalveolar lavage fluids of RSV-infected mice had increased significantly in TiO2-exposed mice compared with the control on day 5 post-infection, but not in uninfected mice. While pulmonary viral titers were not affected by TiO2 exposure, an increase in the infiltration of lymphocytes into the alveolar septa in lung tissues was observed. Immunohistochemical analysis revealed aggregation of TiO2 nanoparticles near inflammatory cells in the severely affected region. Thus, a single exposure to TiO2 nanoparticles affected the immune system and exacerbated pneumonia in RSV-infected mice.

Perinatal exposure to insecticide methamidophos suppressed production of proinflammatory cytokines responding to virus infection in lung tissues in mice.

Methamidophos, a representative organophosphate insecticide, is regulated because of its severe neurotoxicity, but it is suspected of contaminating agricultural foods in many countries due to illicit use. To reveal unknown effects of methamidophos on human health, we evaluated the developmental immunotoxicity of methamidophos using a respiratory syncytial virus (RSV) infection mouse model. Pregnant mice were exposed to methamidophos (10 or 20 ppm) in their drinking water from gestation day 10 to weaning on postnatal day 21. Offsprings born to these dams were intranasally infected with RSV. The levels of interleukin-6 (IL-6) and interferon-gamma in the bronchoalveolar lavage fluids after infection were significantly decreased in offspring mice exposed to methamidophos. Treatment with methamidophos did not affect the pulmonary viral titers but suppressed moderately the inflammation of lung tissues of RSV-infected offspring, histopathologically. DNA microarray analysis revealed that gene expression of the cytokines in the lungs of offspring mice exposed to 20 ppm of methamidophos was apparently suppressed compared with the control. Methamidophos did not suppress IL-6 production in RSV-infected J774.1 cell cultures. Thus, exposure of the mother to methamidophos during pregnancy and nursing was suggested to cause an irregular immune response in the lung tissues in the offspring mice.

Synthesis of 2-methyl 16-membered macrolide derived from tylosin.

To improve the metabolic stability of a 16-membered macrolide, 2-methylated derivatives of desmycosin were synthesized. Among these derivatives, 2beta-methyldesmycosin retained antibacterial activity and showed improved stability in rat serum compared to desmycosin.

In vitro and in vivo antibacterial activities of the tricyclic ketolide TE-802 and its analogs.

The in vitro and in vivo antibacterial activities of tricyclic ketolides (TKs: TE-802, TE-806, TE-935, TE-943) have been compared with those of clarithromycin (CAM), azithromycin (AZM) and rokitamycin (RKM). TKs were active against not only erythromycin (EM)-susceptible organisms; aerobic gram-positive bacteria, some gram-negative bacteria, anaerobic bacteria and Mycoplasma pneumoniae, but also EM-resistant Staphylococcus aureus (inducible macrolide-resistant strains) as well as EM-resistant Streptococcus pneumoniae (efflux-resistant strains). The therapeutic efficacies of TKs against systemic infections and respiratory tract infection (RTI) caused by gram-positive bacteria in mice are superior to those of CAM and AZM. The peak plasma levels (Cmax, p.o.) of TE-802 in mice were equal to that of CAM, but the plasma area under the concentration-time curve (AUC(24 hours)) was 4.7 times that for CAM. The plasma Cmax (p.o.) value for TE-802 in monkey was equal to that of CAM, whereas the AUC(8 hours) value was three-fourths that of CAM. The pharmacokinetics of TE-802 are similar to those of AZM in mice and monkeys, suggesting the potential for once-daily administration in humans.

Persistence of Staphylococcus aureus colonization on the skin of NC/Nga mice.

BACKGROUND: Colonization of Staphylococcus aureus (S. aureus) on skin is one factor which can worsen atopic dermatitis (AD). The reduction of bacterial colonization in these lesions was reported to be effective for the treatment of subjects with AD. NC/Nga mice are recognized to be a model of AD. OBJECTIVE: We examined the susceptibility of S. aureus colonization on the skin in NC/Nga mice, as compared with findings in BALB/c mice. METHODS: The number of S. aureus on the skin was counted and serum corticosterone, serum interferon-gamma (IFN-gamma) and interleukin (IL)-12 levels were measured. The effects of dexamethasone on number of S. aureus on the skin and serum IFN-gamma and interleukin IL-12 levels were also examined. RESULTS: The number of S. aureus increased in parallel with the severity of the dermatitis in these mice, and the remaining number of S. aureus on the skin after topical treatment of S. aureus suspension was higher than that in BALB/c mice. Serum IFN-gamma and IL-12 concentrations in NC/Nga mice were lower than in BALB/c mice, and the circadian variations of serum corticosterone concentrations in NC/Nga mice tended to reveal higher levels compared with the circadian variations in BALB/c mice. Continuous administration of dexamethasone inhibited the elimination of S. aureus from skin surfaces of BALB/c mice. Serum IFN-gamma and IL-12 concentrations in dexamethasone-treated BALB/c mice were lower than those in vehicle-treated BALB/c mice. CONCLUSION: Our data support the notion that high levels of circadian variations of endogenous glucocorticoid lead to a lack of protection against bacteria and a persistence of S. aureus colonization on the skin in NC/Nga mice.