Lung exposure to nanoparticles modulates an asthmatic response in a mouse model.

The aim of this study was to investigate the modulation of an asthmatic response by titanium dioxide (TiO2) or gold (Au) nanoparticles (NPs) in a murine model of diisocyanate-induced asthma. On days 1 and 8, BALB/c mice received 0.3% toluene diisocyanate (TDI) or the vehicle acetone-olive oil (AOO) on the dorsum of both ears (20 µL). On day 14, the mice were oropharyngeally dosed with 40 µL of a NP suspension (0.4 mg·mL⁻¹ (∼0.8 mg·kg⁻¹) TiO2 or Au). 1 day later (day 15), the mice received an oropharyngeal challenge with 0.01% TDI (20 µL). On day 16, airway hyperreactivity (AHR), bronchoalveolar lavage (BAL) cell and cytokine analysis, lung histology, and total serum immunoglobulin E were assessed. NP exposure in sensitised mice led to a two- (TiO2) or three-fold (Au) increase in AHR, and a three- (TiO2) or five-fold (Au) increase in BAL total cell counts, mainly comprising neutrophils and macrophages. The NPs taken up by BAL macrophages were identified by energy dispersive X-ray spectroscopy. Histological analysis revealed increased oedema, epithelial damage and inflammation. In conclusion, these results show that a low, intrapulmonary doses of TiO2 or Au NPs can aggravate pulmonary inflammation and AHR in a mouse model of diisocyanate-induced asthma.

Staphylococcus aureus enterotoxin B facilitates allergic sensitization in experimental asthma.

BACKGROUND: Staphylococcus aureus Enterotoxin B (SEB) has immunomodulatory effects in allergic airway disease. The potential contribution of SEB to the sensitization process to allergens remains obscure. OBJECTIVE: In order to study the effects of staphylococcal-derived toxins on the sensitization to ovalbumin (OVA) and induction of allergic airway inflammation, we have combined the nasal application of OVA with different toxins. METHODS: Nasal applications of OVA and saline, SEA, SEB, toxic shock syndrome toxin (TSST)-1, protein A or lipopolysaccharide (LPS) were performed on alternate days from day 0 till 12. On day 14, mice were killed for the evaluation of OVA-specific IgE, cytokine production by mediastinal lymph node (MLN) cells and bronchial hyperreactivity (BHR) to inhaled metacholine. The effect of SEB on dendritic cell (DC) migration and maturation, and on T cell proliferation was evaluated. RESULTS: Concomitant endonasal application of OVA and SEB resulted in OVA-specific IgE production, whereas this was not found with SEA, TSST-1, protein A, LPS or OVA alone. Increased DC maturation and migration to the draining lymph nodes were observed in OVA/SEB mice, as well as an increased T cell proliferation. Bronchial inflammation with an influx of eosinophils and lymphocytes was demonstrated in OVA/SEB mice, together with hyperresponsiveness and the production of IL-4, IL-5, IL-10 and IL-13 by MLN stimulated with OVA. CONCLUSIONS: Our data demonstrate that SEB facilitates sensitization to OVA and consecutive bronchial inflammation with features of allergic asthma. This is likely due to augmentation of DC migration and maturation, as well as the allergen-specific T cell proliferation upon concomitant OVA and SEB application.

Immunological determinants in a mouse model of chemical-induced asthma after multiple exposures.

In a mouse model of chemical-induced asthma, we investigated the effects of multiple challenges, using toluene diisocyanate (TDI), a known cause of occupational asthma. On days 1 and 7, BALB/c mice received TDI or vehicle (acetone/olive oil). On days 10, 13 and 16 the mice received an intranasal instillation of TDI. Ventilatory function (Penh) was monitored by whole body plethysmography for 40 min after each challenge. Reactivity to methacholine was measured 22 h later. Pulmonary inflammation, TNF-alpha and MIP-2 levels were assessed 24 h after the last challenge by broncho-alveolar lavage (BAL). Other immunological parameters included total IgE, lymphocyte sub-populations in auricular and cervical lymph nodes, and IL-4, IFN-gamma and IL-13 levels in supernatants of lymph node cells, cultured with or without concanavalin A. Early ventilatory function and airway reactivity increased in all groups that received a dermal application and one or multiple intranasal challenges of TDI. After multiple challenges, lung inflammation was characterized by neutrophils (approximately 15%), and eosinophils (approximately 4%), along with an increase in BAL MIP-2 and TNF-alpha levels. The auricular and cervical lymph node cells of all sensitized mice showed an increase in B cells, Th cells and an increased concentration of in vitro release of IL-4, IFN-gamma and IL-13 after stimulation with concanavalin A. Total serum IgE was elevated in dermally TDI-sensitized mice. This protocol including multiple challenges results in a model that resembles human asthma, indicating that responses found in the model using a single challenge could be a good first indication for the development of asthma.

Assessment of the sensitization potential of persulfate salts used for bleaching hair.

BACKGROUND: Persulfate salts have been associated with both allergic contact dermatitis and bronchial asthma. Because there is currently no experimental data available on the sensitizing properties of persulfate salts (ammonium, sodium, and potassium persulfates), we determined their dermal sensitizing capacity, using the murine local lymph node assay (LLNA). MATERIAL AND METHODS: For three consecutive days, BALB/c mice were dermally treated with ammonium, sodium, or potassium persulfate or with the vehicle alone (dimethyl sulfoxide) on each ear (2 x 25 microl). On D6, mice were injected intravenously with [(3)H]-methyl thymidine. The draining auricular lymph nodes were removed, and the incorporation of [(3)H]-methyl thymidine was compared with that of vehicle-treated control mice. A stimulation index (SI) relative to the vehicle-treated control value was derived. The sensitizing potency of the chemicals tested was determined by estimating the concentration of chemical required to induce a SI of 3 (EC3). RESULTS: All three chemicals provoked positive responses in the LLNA, with dose-dependent increases in proliferation. Maximal SIs recorded were 6.8 +/- 1.8, 6.5 +/- 1.2, and 5 +/- 1.0 at 5% for ammonium, sodium or potassium persulfate, respectively. The EC3 values were 1.9%, 0.9%, and 2.4% for ammonium, sodium, and potassium persulfates, respectively. CONCLUSIONS: All three persulfate salts need to be considered strong-to-moderate sensitizers according to the murine LLNA.

Kinetics of an intratracheally administered chromium catalyst in rats.

Chromium-based catalysts are used for the synthesis of polyethylene, but little is known about the hazard and biomonitoring possibilities of this type of chromium for workers who may be occupationally exposed to such compounds. Therefore, the bioavailability and toxicokinetics of chromium were studied in male Wistar rats after a single intratracheal instillation (2 ml/kg body weight) of various doses (1, 5, or 25 mg/kg body weight) of the catalyst (approximately 1% chromium bound to an amorphous silica matrix), either before (CAT-Cr[III]) or after (CAT-Cr[VI]) heat treatment. The results were compared with those of equivalent amounts of two chromium salts (CrCl(3) and K(2) Cr(2) O (7). Each dose group was composed of three rats. The concentration of chromium was determined by atomic absorption spectrometry in urine (collected daily for 7 d) and in plasma, erythrocytes, lung, and liver tissue obtained 2 d (only highest concentration) and 7 d after dosing. On d 2, a significant increase in lung weight was found in the animals treated with the highest dose of the hexavalent Cr products. On d 7, on the basis of body weights, lung weights, and lung histology, there was no overt toxicity, except after the highest dose of CAT-Cr(VI). The elimination of all forms of chromium was apparently monoexponential, with calculated half-life elimination times in urine of 4-11 h for Cr(III) (CAT-Cr[III] and CrCl3 ) and 8-21 h for Cr(VI) (CAT-Cr[VI] and K(2) Cr(2) O(7). On d 2, the erythro-cytes Cr concentrations were significantly higher for the hexavalent Cr products than for the trivalent Cr products. After 7 d, the erythrocytes Cr concentrations were significantly increased above control values (3 microg/L) only in rats treated with the 2 highest doses of Cr( VI) compounds (12 and 64 microg/L for K(2) Cr(2) O(7), and 14 and 79 microg/L for CAT-Cr[VI]). The present study shows that intratracheally instilled Cr(VI) and Cr(III) have different toxicokinetic profiles and that the Cr(VI) catalyst has the same bioavailability and excretion kinetics as a water-soluble Cr(VI) salt. Exposure to chromium compounds could be monitored by measuring Cr concen-trations in urine (shortly after exposure) and in erythrocytes (also at later time points after high Cr[VI] exposure).