A. Casset

Inhaled formaldehyde exposure: effect on bronchial response to mite allergen in sensitized asthma patients

Background:  Formaldehyde, an indoor air pollutant, is known to be an irritant and an etiologic factor in occupational asthma. An epidemiologic study suggests that it may also increase the risk of childhood asthma for concentrations above 60 μg/m3.

Immunomodulatory properties of multi-walled carbon nanotubes in peripheral blood mononuclear cells from healthy subjects and allergic patients

In the present study, we investigated the immunomodulatory activity of multi-walled carbon nanotubes (MWCNTs) in peripheral blood mononuclear cells (PBMCs) from healthy donors and mite-allergic subjects. Freshly prepared PBMCs, stimulated or not with Toll-like receptor (TLR)1-9 agonists, a T cell mitogen (phytohemagglutinin A) or mite allergen extract were cultured in the presence or absence of MWCNTs. Secretion of TNF-α, IL-2, IL-5, IL-6, IL-12/23p40 or IFN-γ was quantified in the culture supernatants by ELISA. Basal secretion of all the cytokines was not altered by MWCNTs in PBMCs from both healthy donors and allergic subjects. In PBMCs from healthy donors, TNF-α, IL-6 and IL-12/23p40 secretion in response to the TLR4 agonist, lipopolysaccharide was however increased in a dose-dependent manner by MWCNTs. Significant increases in the release of these cytokines were also observed in PBMCs stimulated with a TLR2 or TLR3 agonist. MWCNTs also increased the release of IL-2 and IFN-γ by PBMCs stimulated with a T cell mitogen. In contrast, MWCNTs inhibited allergen-induced IL-5 secretion by PBMCs from mite-allergic subjects. As well, MWCNTs altered the capacity of PBMC-derived monocytes to differentiate into functional dendritic cells. All together, our data suggest that according to its immune cell target, MWCNTs may either promote or suppress immune responses in humans. Further investigations are necessary to fully understand the complexity behind interactions of engineered nanoparticles with the immune system.

Exposure to multi-walled carbon nanotubes results in aggravation of airway inflammation and remodeling and in increased production of epithelium-derived innate cytokines in a mouse model of asthma

AbstractWith the development of nanotechnologies, the potential adverse effects of nanomaterials such as multi-walled carbon nanotubes (MWCNT) on the respiratory tract of asthmatics are questioned. Furthermore, investigations are necessary to understand how these effects might arise. In the present study, we hypothesized that epithelium-derived innate cytokines that are considered as important promoting factors in allergy may contribute to an aggravating effect of MWCNT on asthma. We investigated in the mouse the effect of MWCNT on systemic immune response and airway inflammation and remodeling induced by the most frequent allergen so far associated with asthma, house dust mite (HDM), and we examined the production of the innate cytokines thymic stromal lymphopoietin (TSLP), IL-25, IL-33, and GM-CSF. Mice exposed to HDM exhibited specific IgG1 in serum and inflammatory cell infiltration, and increased Th2 cytokine production, mucus hyperproduction, and collagen deposition in the airways when compared to naïve animals. Levels of total IgG1 and HDM-specific IgG1, influx of macrophages, eosinophils and neutrophils, production of collagen, TGF-β1, and mucus, as well as levels of IL-13, eotaxin, and TARC, were dose-dependently increased in mice exposed to HDM and MWCNT compared to HDM alone. These effects were associated with an increased production of TSLP, IL-25, IL-33, and GM-CSF in the airways. Our data demonstrate that MWCNT increase in a dose-dependent manner systemic immune response, as well as airway allergic inflammation and remodeling induced by HDM in the mouse. Our data suggest also a role for airway epithelium and innate cytokines in these effects.

Niox® and Niox Mino®: comparison of exhaled NO in grass pollen allergic adult volunteers

Marchi M, Sabatini A, Nardi R et al. Prevalence estimates of chronic diseases in Italy: exploring the differences between selfreport and primary care databases. J Public Health Med 2003;25:254–257. 5. Filippi A, Vannuzzo D, Bignamini AA, Sessa E, Brignoli O, Mazzaglia G. Computerised general practice databases provides quick and cost-effective information about prevalence of angina pectoris. Ital Heart J 2005;6:49–51. 6. Lawrenson R, Williams T, Farmer R. Clinical information for research; the use of general practice databases. J Public Health Med 1999;21:299–304. 7. Bousquet J, van Cauwenberge P, Ait Khaled N, Bachert C, Baena-Cagnani CE, Bouchard J et al. Pharmacologic and antiIgE treatment of allergic rhinitis ARIA update (in collaboration with GALEN). Allergy 2006;61:1086–1096.

Low-dose endotoxin in allergic asthmatics : effect on bronchial and inflammatory response to cat allergen

Background Endotoxin was proposed to increase the severity of asthma. Endotoxin levels greatly differ according to settings. In domestic environments, airborne concentrations may be dramatically low compared with levels reported in occupational settings.

Formaldehyde interferes with airway epithelium integrity and functions in a dose- and time-dependent manner

Formaldehyde (HCHO) is a common indoor air pollutant. To assess its potential role and mechanism of action in asthma, we exposed the bronchial epithelial cell lines Calu-3 and 16HBE to HCHO (70-7000 μM) according to two exposure schedules (30 min and 24 h), before measuring cell viability, necrosis and apoptosis, reactive oxygen species production, cytokine release, as well as trans-epithelial electrical resistance (TEER) of cell monolayers. Whereas exposure to HCHO for 30 min had a limited effect on cell viability, exposure for 24h to 1400-7000 μM HCHO induced a pronounced dose-dependent cell death. The important decrease in cell viability observed after 24h exposure to the highest concentrations of HCHO (1400-7000 μM) was accompanied by important LDH release and ROS production, whereas a 4h exposure to lower HCHO concentrations (350 μM) induced cell apoptosis. Also, exposure to HCHO for 30 min dose-dependently inhibited basal and lipopolysaccharide-induced interleukin-6 (IL-6) and IL-8 production by bronchial epithelial cells. As well, HCHO triggered a dose- and time-dependent decrease in TEER of Calu-3 cell monolayers. The present work demonstrates that HCHO interferes with airway epithelium integrity and functions, and may thus modulate the onset and the severity of asthma. However, importantly, conditions of exposure to HCHO, e.g. level and duration, are determinant in the nature of the effects triggered by the pollutant.

Indoor dust and air concentrations of endotoxin in urban and rural environments.

Studies in European children from a farming background have shown that these children have a reduced risk of asthma and atopic sensitization compared to their urban counterparts. It has been suggested that this might be due to exposure to high levels of endotoxin in the farming environment. The aim of this study was to compare indoor endotoxin concentrations in air and dust samples from randomly selected urban and rural dwellings. In the rural area, endotoxins were analysed in farmhouses and nonfarmhouses as well as housing characteristics, lifestyle factors and agricultural practices likely to influence air and dust endotoxin levels. Endotoxin levels were significantly higher in floor (6600 ± 6100 vs 3600 ± 5600 and 3800 ± 17 000 ng g−1; P < 0·001) and mattress dust (2900 ± 4100 vs 1100 ± 2400 and 800 ± 2600 ng g−1; P < 0·001) from farmhouses compared to other rural and urban homes. However, no difference was observed between endotoxin concentrations in the air of urban and rural houses, and airborne endotoxin levels did not correlate to dust levels. Lack of ventilation and direct entry into the house were correlated with an increase in dust endotoxin levels. These results confirm that dairy farming is associated with high exposure to endotoxins in indoor dust samples. No difference was observed between indoor airborne concentrations between urban and rural houses. These results suggest that measuring endotoxin in dust is the most relevant method to assess endotoxin exposure.

Effets sur la santé des composés organiques volatils de l’habitat

Introduction Lʼhomme est expose durant sa vie a des substances chimiques variees qui appartiennent pour un grand nombre au groupe des Composes Organiques Volatils (COV). Etat des connaissances Les premieres etudes epidemiologiques, transversales, ont revele l’existence d’un lien entre des symptomes respiratoires et une exposition a des concentrations plus elevees de COV. Plus recemment, les resultats d’etudes longitudinales semblent suggerer l’implication d’une exposition aux COV tant dans la modification de la reponse immune lors d’une exposition maternelle, que dans l’apparition de la sensibilisation ou dans l’augmentation du risque d’asthme et de symptomes respiratoires. Conclusions et perspectives Si d’autres etudes sont encore necessaires pour comprendre les mecanismes sous-jacents a ces differents effets sur la sante, une meilleure connaissance de l’exposition aux COV, qui passera par la realisation de mesures des concentrations specifiquement pour chaque compose ou famille de composes mais aussi par la recherche des sources d’exposition, devrait permettre de proposer l’amenagement d’environnements interieurs avec une exposition reduite aux COV dans le but de prevenir leurs effets sur la sante.

Asthma management and inhalation techniques among community pharmacists in 2009: a comparison with the 1999 survey

Abstract Objective: In a 1999 survey, community pharmacists from the Alsace region of France had a reasonably good knowledge of asthma treatment and prevention, but their skill in the use of asthma inhalation devices left room for improvement. Since then, health authorities have encouraged the involvement of community pharmacists in patient care and education in order to improve asthma control. The aim of this study was to assess the change in the knowledge of asthma management and inhaler technique skills of community pharmacists in the same geographic area after a 10-year interval. Methods: In 2009, 86 randomly selected community pharmacists from the Alsace region answered a standardized questionnaire about their theoretical knowledge of and practical attitude toward asthma management and inhaled delivery systems, following which their skills in the use of four inhalation devices (pressurized metered-dose inhaler (pMDI) with/without a spacer, breath-actuated pMDI and dry powder inhaler (DPI)) were evaluated. Results: Very few pharmacists were required to manage an acute asthma exacerbation at the pharmacy, but all responded well by administering a short-acting inhaled β2-agonist. Theoretical knowledge of asthma management (criteria of severity of asthma exacerbation, guidelines and drugs triggering asthma exacerbations) was still average. Compared with 1999, they were twice as confident in demonstrating inhaler use, and their skills in using the pMDI, breath-actuated pMDI and DPI had improved significantly (p < 0.001). Conclusions: Since 1999, pharmacists’ skill in the use of inhalers has improved, but theoretical knowledge of asthma management is still average, pointing to the importance of continuing pharmaceutical education.

A dynamic system for single and repeated exposure of airway epithelial cells to gaseous pollutants.

In vitro models are promising approaches to investigate the adverse effects and the mode of action of air pollutants on the respiratory tract. We designed a dynamic system that allows the single or repeated exposure of cultured cells to two major indoor air gaseous pollutants, formaldehyde (HCHO) and nitrogen dioxide (NO2), alone or as a mixture. In this system, the Calu-3 human bronchial epithelial cell line was exposed at the air-liquid interface (ALI) or submerged by culture medium to synthetic air or to target concentrations of HCHO and/or NO2 once or on 4 consecutive days before assessment of cell viability and necrosis, IL-6 and IL-8 release and trans-epithelial electrical resistance. Our data showed that whereas the ALI method can be used for single short-term exposures only, the submerged method provides the possibility to expose Calu-3 cells in a repeated manner. As well, we found that repeated exposures of the cells to HCHO and NO2 at concentrations that can be found indoors triggered a significant decrease in cell metabolism and an increase in IL-8 release that were not evoked by a single exposure. Thus, our work highlights the fact that the development of systems and methods that allow repeated exposures of cultured cells to gaseous compounds in mixtures is of major interest to evaluate the impact of air pollution on the respiratory tract.