Nanotoxicology of Fine PM: The Role of Surfactant and Collectins in Short-Term Health Effects of PM Air Pollution

This exploratory proposal brings together three institutions in a new collaboration to investigate the mechanism by which nanoparticles enter the body and cause damage to lung and circulatory systems. It is well known that fine particles can cause sickness and death when breathed in over short and long periods. The observed health effects are similar for different types of particles but relate to particle size and surface. This suggests that particle size and surface area produce a physical response and are important determinants of the problem. The health effects of PM exposure are widespread in the UK and globally, resulting in significant ill health and associated costs. Particles inhaled from the air first deposit in lung fluid lining the air sacs in the lung. This is the first contact the particles have with the lung, and the body immediately acts to defend against the invading particle. One of the first interactions between the particles and the fluid is the attachment of surfactant and collectins to particle surfaces to modify macrophage phagocytosis and host immunological responses. The collectins SP-A and SP-D are known to be involved in pathogenic particle clearance via macrophage recognition, and dictate the effectiveness of infectious particle removal. Inhibition or overload of this process may therefore lead to the observed health effects on PM exposure, such as increased infections in PM exposed animals and humans. Sequestration of these collectins on large PM surface areas depositing to the lunng may cause increased vulnerability in compromised individuals. Such processes would explain the short-term health effects observed in sick or vulnerable individuals exposed to PM. It will also influence the health effects observed following longterm exposures. The purpose of this project is to understand the particles from an environmental point of view, study the physical characteristics of the particles by physical techniques, then to vary the immunological effects of the particles by placing different molecules on the particle surfaces. The objective is to define a more detailed project which will follow from this exploratory study. The Dept of Chemical Engineering, Birmingham University is a leader in the field of chemicals, pharmaceuticals, food, environmental engineering and emerging areas such as nanotechnology. Chemical Engineering received a top research rating of 5* in 2001, one of only three Chemical Engineering departments in the country to do so. Prof Kendall FRS, a leading expert in nanotechnology and molecular forces, is PI for this proposal. The MRC Immunology Unit is in one of only three Departments of Biochemistry in the country to receive a 5 (A) rating in the last Research Assessment Exercise. Dr Clark BA MA MB BChir MD (Cantab) MA DPhil (Oxon) MRCP MRCPCH has significant international experience and recognition in the field of innate immunity, especially with respect to the structure and function of the lung collectins, SP- A and -D and their interactions with inhaled microorganisms, allergens and cells of the immune system. The Visiting Researcher, Dr Michaela Kendall, was awarded the prestigious HEI Walter Rosenblith New Investigator Award in 2004 and is Assistant Professor at the Medical School, Uludag University. She is an expert air pollution scientist, specialising in characterising particulate matter and relating that data to health effects observed in epidemiology studies. The work proposed here stems from a small grant originally awarded by the UK Department of Health (DoH) in 1999. All the proposal collaborators named here are internationally recognised British scientists, representing UK science in the global scientific community. All investigators are regularly invited to participate in international events as invited speakers, reviewers and collaborators, ensuring an international dimension to this project. This enables leveraging of funding from non-UK funding source