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

这一探索性的建议将三个机构聚集在一起进行新的合作，以研究纳米颗粒进入人体并对肺部和循环系统造成损害的机制。众所周知，细颗粒物在短时间和长时间吸入时都会导致疾病和死亡。观察到的健康影响对于不同类型的颗粒是相似的，但与颗粒大小和表面有关。这表明，颗粒大小和表面积会产生物理反应，是问题的重要决定因素。PM暴露对健康的影响在英国和全球都很普遍，导致严重的健康不良和相关成本。从空气中吸入的颗粒物首先沉积在肺内气囊内的肺液中。这是微粒与肺的第一次接触，身体立即采取行动防御入侵的微粒。颗粒和流体之间最早的相互作用之一是将表面活性物质和集合素附着到颗粒表面，以改变巨噬细胞的吞噬作用和宿主的免疫反应。已知集合素SP-A和SP-D通过巨噬细胞识别参与病原性颗粒的清除，并决定感染性颗粒的清除效果。因此，抑制或过载这一过程可能会导致观察到的PM暴露对健康的影响，如PM暴露动物和人类感染增加。将这些收集素隔离在大片PM表面积上，沉积到LUNNG中，可能会导致受危害个人的脆弱性增加。这些过程将解释暴露在PM下的病人或易受伤害的人的短期健康影响它还将影响长期暴露后观察到的健康影响。本项目的目的是从环境角度了解颗粒，通过物理技术研究颗粒的物理特性，然后通过在颗粒表面放置不同的分子来改变颗粒的免疫效果。目标是确定从这项探索性研究中得出的更详细的项目。伯明翰大学化学工程系在化学、制药、食品、环境工程和纳米技术等新兴领域处于领先地位。2001年，化学工程获得了5*的最高研究评级，这是全国仅有的三个获得此殊荣的化学工程系之一。Kendall FRS教授是纳米技术和分子力方面的领先专家，他是这项提议的PI。MRC免疫科是该国仅有的三个在上一次研究评估中获得5(A)评级的生化部门之一。Clark BA MA MB BChir MD(Canab)MA DPhil(Oxon)MRCP MRCPCH博士在先天性免疫领域拥有丰富的国际经验和认可，特别是在肺集合素、SP-A和-D的结构和功能以及它们与吸入微生物、过敏原和免疫系统细胞的相互作用方面。访问研究员Michaela Kendall博士于2004年被授予享有盛誉的HeI Walter Rosenblith新研究员奖，是乌卢达格大学医学院的助理教授。她是一位空气污染专家，专门研究颗粒物的特征，并将这些数据与流行病学研究中观察到的健康影响联系起来。这里提出的工作源于1999年英国卫生部(DoH)最初授予的一小笔赠款。这里提到的所有提案合作者都是国际公认的英国科学家，在全球科学界代表英国科学。所有调查人员定期被邀请作为特邀演讲人、审查员和合作者参加国际活动，以确保该项目具有国际性。这使得能够利用来自非英国资金来源的资金

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