Nano-sized versus larger particles: Does extremely small size introduce unique mechanisms for particle-induced toxicity?

Nanoparticles (NP) have been suggested to be important factors in inducing lung and heart disease of particulate air pollution (PM), and are also increasingly used in industry and medicine. Thus, there is an increasing concern for both public and occupati onal exposure. Generally, inflammation is known to play a key role in both lung and heart diseases. PM, and possibly NP, are known to be involved in such processes. The main focus of this project will be to examine whether NP represent an increased healt h hazard compared to larger particles, not only due to an increased surface area to mass ratio, but to the small size (due to different handling by the cells) and/or inherent physical properties. An important issue is whether the NP causes a change in res ponse pattern compared to larger PM, and whether this occurs via qualitative or quantitative changes in intracellular signalling. This will be studied in different target cells; epithelial lung cells, alveolar macrophages, cardiomyocytes and -fibroblasts. The target cells will be exposed to NP and larger particles of the same material, and examined for changes in intracellular signalling and inflammatory responses in relation to surface area. The knowledge of how NP interacts with lung cells is limited, b ut our collaborators have shown that oxidative stress and calcium are involved. How these NP-induced changes are linked to other intracellular events are less known. In the present project we want, in addition to examine the importance of size, to extend these mechanistic studies both in lung and heart cells. This will be done by examining the role of NP-induced oxidative stress versus membrane receptor-linked changes, and the connection to intracellular signalling (src-, MAP-kinases) and activation of tr anscription factors (AP-1, NFκB). The project will be a joint effort including investigators in our department, national and international coworkers, and will be developed in tight contact with ongoing projects