Mechanisms of anti-apoptotic effects induced by inhalable nanoparticles in neutrophilic granulocytes

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Inhaled hydrophobic nanoparticles induce inflammatory reactions of the airways which are dominated by neutrophilic granulocytes. In humans exposed to environmental nanoparticles this neutrophilic lung inflammation can significantly contribute to the development of diseases like chronic obstructive pulmonary disease (COPD) or cardiovascular diseases. Earlier studies of the applicant for the first time demonstrated that carbon nanoparticles not only trigger neutrophilic lung inflammation but also enhance the inflammatory reaction at the level of the neutrophils. In human neutrophilic granulocytes exposure to carbon nanoparticles leads to a suppression of the natural apoptosis rate and therefore to a prolongation of the cellular life span and an enhancement of the inflammatory reaction. Using an intervention strategy based on the stabilisation of the membrane compartment of cells, the causality of these findings could be corroborated in an in vivo system and in a human study. Due to the rapid development of nanotechnology, humans may be exposed to different kinds of nanoparticles. One aim of the project is to understand the cellular and molecular mechanisms leading to the delay of neutrophil apoptosis by nanoparticles. As exposure with carbon nanoparticles leads to intracellular oxidative stress, the causality of the induction of reactive oxygen species for the delay of apoptosis will be studied with appropriate anti-oxidative strategies. As cause for the induction of oxidative stress, on one hand side the intrinsic oxidative potential of nanoparticles will be tested by the use of model particles differing with respect to their oxidative capacity. On the other hand side, oxidative systems of the cell will be investigated by the use of pharmacological inhibitors and a knock out strategy. Furthermore, the relevance of membrane-coupled signalling events will be investigated at the level of lipid raft structures. Again the causality of such events will be studied by intervention strategies. Another aim is to evaluate particle properties like chemical composition, size, reactive surface, and oxidative potential for their relevance for the anti-apoptotic effects of nanomaterials. This will be studied using a selection of nanomaterials to which humans are exposed. The potential of the materials to prolong the neutrophilic life span will be estimated by time series and dose response experiments. Besides ex vivo studies with human neutrophils, experiments using the animal model of pharyngeal aspiration of nanoparticles will be performed. The delay of neutrophil apoptosis will be monitored in broncho-alveolar lavage from exposed animals.