Respiratory sensitisation in humans: Characterisation of pulmonary epithelial:dendritic cell interactions

人类呼吸致敏：肺上皮的表征：树突状细胞相互作用

• 批准号: BB/D018617/1
• 负责人: Teresa Dorothy Tetley
• 金额: $ 24.7万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FD018617%2F1
• 关键词: Respiratory; sensitisation; humans; Characterisation; pulmonary

We are exposed to a range of chemicals in day-to-day life, at home and at work, which may have unwanted health effects. In this study we are interested in the sensitivity of the lung to chemicals that are inhaled, usually while at work. Not everybody is affected, but when those who are affected are exposed to the same chemical again they may experience an asthma attack, and they may also react to other agents that they inhale from the air (this accounts for approximately 10% of adult-onset asthma). This is called respiratory sensitisation. It is important to determine whether existing or newly-developed chemicals will cause respiratory sensitisation, and if so, the magnitude of the response. It is also important to understand the cellular mechanisms that are involved. The immunological responses of the lung are complex, and no validated tests exist to determine the potential of chemicals to initiate these responses. Animal experiments are often used to help make these assessments, but they are not always very accurate, although they do help us understand some of the mechanisms involved. Furthermore, the 7th Amendment to the European Union Cosmetics Directive (European Commission, 2003) recommends that we develop new ways of testing compounds so that we reduce animal experimentation. The strategy is called the 3Rs, Reduction, Refinement and Replacement of the use of animals in scientific tests. One aim of this study is to establish testing methods that avoid using animals by using human cells. Use of human cells is important as it will ensure development of a more representative model for assessing the potency of these chemicals in man. The cells in the lung that respond to inhaled particles are the lung's 'skin', epithelial cells, as well as cells that act like a vacuum cleaner, internalising and neutralising inhaled material that settles on the 'skin'; which are called macrophages. Epithelial cells and macrophages send messages to dendritic cells that sit underneath the lung epithelial cells. Dendritic cells also extend long 'probes' onto the epithelial surface where they can directly interact with any inhaled chemicals. Depending on the messages received, dendritic cells then activate the immune response to fight infection and other foreign particles that reach the lung. However, sometimes the messages go wrong, and this is when the lung becomes very sensitive to some types of inhaled particles and chemicals. We aim to isolate cells from adult human lung tissue that is removed during an operation to remove a tumour. Normal regions of lung that are attached to, but not affected by, the tumour can be used. We will then culture epithelial, macrophage and dendritic cells alone, and together in a 3-dimensional model resembling the lung. We will expose the cells to chemicals that we know are respiratory sensitisers, as well as chemicals that do not cause respiratory sensitisation, to examine the cellular messaging pathways involved in respiratory sensitisation. We also want to determine whether there are unique responses that identify chemical sensitisers so that these culture models can be developed and used for routine testing of existing and new compounds that might affect the lung. In addition, with this knowledge, it should be possible to develop drugs that prevent these abnormal responses. These models could be used to avoid the use of animals to investigate respiratory sensitisers to understand mechanisms of respiratory sensitisation.

我们在日常生活中，在家中和工作中接触一系列化学物质，这可能会产生不必要的健康影响。在这项研究中，我们对肺对被吸入的化学物质的敏感性感兴趣，通常在工作中。并非每个人都受到影响，但是当受影响的人再次接触到同一化学物质时，他们可能会遭受哮喘发作，并且他们也可能会对他们从空中吸入的其他代理人做出反应（这约占成人发病的10％哮喘）。这称为呼吸敏化。确定现有化学物质是否会导致呼吸敏化，如果是，则重要的是反应的大小，这一点很重要。了解所涉及的细胞机制也很重要。肺的免疫反应很复杂，并且没有经过验证的测试来确定化学物质启动这些反应的潜力。动物实验通常用于帮助进行这些评估，但是它们并不总是非常准确，尽管它们确实可以帮助我们了解涉及的某些机制。此外，《欧盟化妆品指令》的第七修正案（欧洲委员会，2003年）建议我们开发测试化合物的新方法，以便减少动物实验。该策略称为3RS，减少，改进和替代动物在科学测试中的使用。这项研究的目的之一是建立测试方法，以避免使用人类细胞使用动物。人类细胞的使用非常重要，因为它将确保开发更具代表性的模型来评估人类中这些化学物质的效力。对吸入颗粒反应的肺部细胞是肺的“皮肤”，上皮细胞，以及像真空清洁剂一样，内在化和中和的吸入材料，这些材料沉淀在“皮肤”上；称为巨噬细胞。上皮细胞和巨噬细胞向位于肺上皮细胞下方的树突状细胞发送消息。树突状细胞还将长的“探针”延伸到上皮表面，它们可以直接与任何吸入化学物质相互作用。根据收到的消息，树突状细胞随后激活了对抗感染和其他到达肺部的外粒子的免疫反应。但是，有时消息出错，这是肺对某些类型的吸入颗粒和化学物质非常敏感的时候。我们的目标是将细胞与成年人类肺组织分离，该细胞在手术过程中被去除以去除肿瘤。可以使用肿瘤的正常肺部正常区域。然后，我们将单独培养上皮，巨噬细胞和树突状细胞，并在类似于肺部的三维模型中一起培养上皮细胞。我们将使细胞暴露于我们知道的化学物质中，这些化学物质是呼吸道感觉到的，以及不会引起呼吸敏化的化学物质，以检查与呼吸敏化有关的细胞消息传递途径。我们还想确定是否存在识别化学感觉剂的独特反应，以便可以开发这些培养模型并用于常规测试可能影响肺的现有和新化合物。此外，凭借这些知识，应该有可能开发防止这些异常反应的药物。这些模型可用于避免使用动物来研究呼吸道感官，以了解呼吸敏化的机制。

项目成果

Modeling In Vivo Interactions of Engineered Nanoparticles in the Pulmonary Alveolar Lining Fluid.

• DOI: 10.3390/nano5031223
• 发表时间: 2015-09
• 期刊: Nanomaterials (Basel, Switzerland)
• 作者: Mukherjee D;Porter A;Ryan M;Schwander S;Chung KF;Tetley T;Zhang J;Georgopoulos P
• 通讯作者: Georgopoulos P

Expression of blood dendritic cell antigens (BDCAs) by CD1a+ human pulmonary cells.

CD1a 人肺细胞表达血液树突状细胞抗原 (BDCA)。

• DOI: 10.1016/j.rmed.2009.02.006
• 发表时间: 2009
• 期刊: Respiratory medicine
• 影响因子: 4.3
• 作者: Tsoumakidou M