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Physiologically-based kinetic (PBK) modeling is a valuable tool to understand the kinetics of nanoparticles (NPs) in vivo. However, estimating PBK parameters remains challenging and commonly requires animal studies. To develop predictive models to estimate PBK parameter values based on NP characteristics, a database containing PBK parameter values and corresponding NP characteristics is needed. As a first step toward this objective, this study estimates PBK parameters for gold NPs (AuNPs) and provides a comparison of two different NPs. Two animal experiments are conducted in which varying doses of AuNPs attached with polyethylene glycol (PEG) are administered intravenously to rats. The resulting Au concentrations are used to estimate PBK model parameters. The parameters are compared with PBK parameters previously estimated for poly(alkyl cyanoacrylate) NPs loaded with cabazitaxel and for LipImage 815. This study shows that a small initial database of PBK parameters collected for three NPs is already sufficient to formulate new hypotheses on NP characteristics that may be predictive of PBK parameter values. Further research should focus on developing a larger database and on developing quantitative models to predict PBK parameter values.

Exposure of humans to metal oxide nanoparticles (NPs) occurs mainly via air, and inhaled metal oxide NPs may generate inflammation. The aim of this study was to investigate the proinflammatory potential of six metal oxide NPs (CeO2, Mn2O3, CuO, ZnO, Co3O4 and WO3; 27–108 μg ml−1) using human primary 3-dimensional airway epithelium (MucilAir™) and dendritic cell (DC) models. Metal oxide NPs were mainly aggregated/agglomerated in the cell media, as determined by dynamic light scattering, scanning electron microscopy and differential centrifugal sedimentation. WO3 and ZnO were highly soluble, both with and without respiratory mucus. Proinflammatory signalling by the epithelium was evaluated after a 24 hour exposure by increased interleukin-6 and -8 and monocyte chemoattractant protein 1 cytokine release, which occurred only for CuO. Moreover, maturation of immature human DCs, which play a key role in the lung immune system, were evaluated by expression of surface markers HLA-DR, CD80, CD83 and CD86 after a 48 hour exposure. Only Mn2O3 consistently upregulated DC maturation markers. Furthermore, by addition of medium from metal oxide NP-exposed 3-dimensional airway cultures to metal oxide NP-exposed DC cultures, the interplay between lung epithelium and DCs was studied. Such an interplay was again only observed for Mn2O3 and in one of five DC donors. Our results show that, even when using dosages that represent very high in vivo exposure levels, up to 27 hours of constant human airway exposure, metal oxide NPs cause minimal proinflammatory effects and that epithelial cells not necessarily interfere with DC maturation upon metal oxide NP exposure. The present approach exemplifies a relevant translation towards human safety assessment. Copyright © 2017 John Wiley & Sons, Ltd.

Background: Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have anti-inflammatory and immuno-modulating properties which are effective in the treatment of cardiovascular disease and in suppressing the symptoms of ongoing autoimmunity. On the other hand, these anti-inflammatory and immuno-modulating effects may facilitate the development of autoimmunity potentially resulting in autoimmune diseases such as rheumatic diseases. Objectives: To determine whether ACE inhibitors and ARBs use was associated with an increased risk of incident rheumatoid arthritis (RA). Methods: A matched case-control study was conducted among antihypertensive patients using the Netherlands Information Network of General Practice (LINH) database from 2001 through 2006. Cases were patients over 40 years of age with a first-time diagnosis of RA. Each case was matched to up to five controls for age, sex, and index date which was selected one year before the first diagnosis of RA. ACE inhibitors and ARBs exposure was considered to be any prescription issued in the period before index date. Logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CI). Results: Our study included 211 cases and 667 matched controls. After controlling for potential confounders, users of ACE inhibitors or ARBs had adjusted ORs of 1.10 (95% CI: 0.77–1.57) and 1.06 (0.74–1.53), respectively. The adjusted ORs of incident RA among current and past users of ACE inhibitors were 1.14 (0.73–1.77) and 0.60 (0.27–1.30). Current and past use of ARBs had adjusted ORs of 1.38 (0.79–2.41) and 0.27 (0.05–1.51), respectively. Conclusions: Use of ACE inhibitors or ARBs is not associated with an increased risk of developing RA. (aut. ref.)

Exposure to ultraviolet light, especially UVB wavelengths, can impair immune responses in animals and humans. It is remarkable that this immunomodulation is not restricted to the exposed skin but is also found at other sites, i.e. systemic (distant) immunosuppression. A frequently proposed hypothesis is that UVB exposure inhibits, specifically, T helper 1 (Th1)-mediated immune responses. The major reason for this is that contact hypersensitivity (CHS) and delayed-type hypersensitivity (DTH), both Th1-mediated immune responses, are very sensitive to UVB. For this reason these models are frequently used for photoimmunology studies. In the present study, the effects of UVB exposure were investigated in classical models for Th1-mediated immunity, i.e. CHS models in which picrylchloride or oxazolone were used as low-molecular-weight chemical antigens. In these models, CHS responsiveness and cytokines were measured, the latter by both reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The CHS responses to both contact sensitizers (picrylchloride and oxazolone) were suppressed significantly by pre-exposure to repeated suberythemal UVB exposure. Interferon-gamma (IFN-gamma), interleukin (IL)-12 and IL-4, but not IL-10, were detectable in spleen and draining lymph nodes of sensitized BALB/c mice. Repeated UVB exposure prior to sensitization at a distant locus inhibited both IFN-gamma and IL-12 but not IL-4. In BALB/c mice sensitized with ovalbumin (OVA) in the absence of complete Freund's adjuvant, a model for Th2-mediated immunity, OVA-specific serum IgE and cytokine profiles in the spleen were analysed. Sensitization did lead to a significant increase in OVA-specific IgE serum titres. Pre-exposure to UVB resulted in a decreased OVA-specific IgE serum titre. Both RT-PCR and ELISA showed increased levels of IFN-gamma, IL-4 and IL-10 in the spleens of OVA-sensitized mice. The production of IFN-gamma and IL-4 was not affected by UVB pre-exposure. In contrast, the production of IL-10 was significantly increased. This was probably caused by an up-regulation of Th2 cells. It is remarkable that IFN-gamma is significantly suppressed by UVB in Th1-mediated immune reactions but not in Th2-mediated immune reactions where it even appears to increase. IL-10, which is up-regulated by UVB pre-exposure and produced by, among others, Th2 cells, may represent a shift from Th1- to Th2-mediated immune mechanisms. However, IL-10 can also inhibit Th2 responses, which might be the reason for a decreased IgE titre in the Th2 model. From the results of this study it is concluded that UVB exposure prior to sensitization/immunization not only inhibits Th1-mediated but also Th2-mediated immune responses.