Role of autophagy in the respiratory effects of nanoparticles – Nanautophagie

Although great advancements, including in the medical field, can be predicted thanks to the development of nanotechnologies, concerns are growing because of the potential effects of manufactured nanoparticles (MNP) on human health. This is particularly true for the respiratory tract, because it represents a major portal of entry for nanoparticles into the body. For several years, a large amount of studies on nanoparticle’s respiratory toxicity have been published, showing that exposure to nanoparticles can induce lung-remodeling effects (fibrosis, emphysema, …). The induction of an oxidative stress and a pro-inflammatory response are proposed as essential mechanisms of these effects, although the exact underlying molecular mechanisms still remain unknown. From these studies, it is also proposed that each MNP behaves singularly, as a function of its physico-chemical characteristics, although the relevance of each of these determinants is far from understood.
Autophagy is an evolutionary conserved and strictly controlled signaling pathway that allows, among others, degradation of cytoplasmic material and organelles. Autophagy is a central pillar of cellular homeostasis. Several studies strongly suggest a key role of autophagy in the pathogenesis and/or progression of human diseases such as cancer, and neurodegenerative, cardiovascular and inflammatory diseases. These effects of autophagy may be linked to its ability to inhibit inflammatory and oxidative responses.
Taking into account the critical role of autophagy in limiting inflammation and oxidative stress, the hypothesis of this project is that a defective autophagy process could represent a new mechanism explaining, at least in part, MNP-induced inflammation and oxidative stress. The main objective of this project is to understand the cellular mechanisms underlying MNP effects, with a particular focus on autophagy modulation and its consequences in terms of toxicity induced by these materials. Since the respiratory system is the main portal of entry of nanoparticles into the body, we will concentrate on the respiratory effects of MNP and their link with autophagy. We will focus on three chemically different MNP: titanium dioxide, gold and carbon, because of their already large uses and applications. For each nanoparticle, the effects of the modulation of several physico-chemical characteristics (size, surface properties/surface embedding) will be studied. All NP will be synthesized as needed, by on of the partner of the project. Experiments will be performed on pulmonary cells (macrophages, fibroblasts and epithelial cells - primary cultures and cell lines), as well as on mice exposed to nanoparticles by oro-pharyngeal instillation.
The specific scientific aims of the project will be: i) to characterize, in vitro and in vivo, the autophagy in response to the different MNP, investigating the link between autophagic response and the physico-chemical characteristics of the nanoparticles, and ii) to characterize the role of autophagy in the pulmonary response to nanoparticles (in terms of inflammation, oxidative stress and fibrosis). This will be performed by the use of pharmaceutical agents (activators or repressors of autophagy) as well as genetic engineering strategies.
Taken together, this project will generate consistent new knowledge on the health impact of MNP exposure. Expanding knowledge of the implications and biological significance of autophagy dysfunction has tremendous potential to aid in our understanding of nanotechnology risks, design of safer nanomaterials and nanomedicines.