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Advanced Biomaterials and Devices in Medicine
June 2015, Volume 2, Issue 1, pp 1-9
Assessment of respiratory sensitizers: Cytokine responses in a 3D alveolo-capillary barrier model in vitro
M.I. Hermanns1*, J. Kasper1, R.E. Unger1, G. Carpentier2, E.L. Roggen3, C.J. Kirkpatrick1
1 Institute of Pathology, Johannes Gutenberg-University Mainz, 55122 Germany
2 Faculte des Sciences et Technologie, Universite Paris Est Creteil Val-de-Marne, 94000 France
3 Novozymes, Bagsvaerd, 2880 Denmark
* Corresponding author: Dr. rer. nat. Iris Hermanns, e-mail: iris.hermanns@unimedizin-mainz.de
Abstract
Inhalation of high- and low-molecular weight chemicals is a leading cause of allergic respiratory diseases. Respiratory epithelium has not only a barrier function, but contributes to pathogenesis via immuno-modulatory effector mechanisms. In this context, the epithelium is the first cell-type which primarily interacts with inhaled allergens. Our aim was to investigate the in vitro effects of respiratory sensitizers (trimellitic anhydride (TMA), diphenylmethane diisocyanate (MDI), ammonium hexachloroplatinate IV (HCPt) and three enzymes) on specific cells of the human distal lung barrier. We examined the influence of these compounds on a human lung epithelial cell line with characteristics of alveolar type II and Clara cells (NCI H441) and on the microvascular endothelial cell line (ISO-HAS-1) in an established co-culture model of the alveolo-capillary barrier. Apical exposure (inhalative exposure) to subtoxic doses of the compounds (maximum of 25% loss of barrier integrity compared to vehicle control) did not markedly affect the barrier function. However, a clear compartmentalized cytokine release was detected. All respiratory sensitizers (HCPt, TMA, MDI and enzymes) induced a specific cytokine release pattern in the basolateral compartment (corresponding to the vascular lumen) after apical exposure, whereas dermal sensitizers (DNCB, CA and the irritant SA) did not show such an effect. This immuno-modulatory effector mechanism could be a possible contribution of the distal lung epithelial and endothelial cells to the pathogenesis of respiratory sensitization. Our data suggest that measuring a basolateral release of cytokines in apically exposed co-cultures may represent a promising in vitro model for the screening of potential chemical respiratory allergens.
Keywords: 3D tissues, in vitro, proinflammatory cytokines, respiratory toxicity, sensitizer
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