School of Biosciences, Cardiff University, Wales, UK.
Altern Lab Anim. 2011 May;39(2):121-30. doi: 10.1177/026119291103900201.
The respiratory system acts as a portal into the human body for airborne materials, which may gain access via the administration of medicines or inadvertently during inhalation of ambient air (e.g. air pollution). The burden of lung disease has been continuously increasing, to the point where it now represents a major cause of human morbidity and mortality worldwide. In the UK, more people die from respiratory disease than from coronary heart disease or non-respiratory cancer. For this reason alone, gaining an understanding of mechanisms of human lung biology, especially in injury and repair events, is now a principal focus within the field of respiratory medicine. Animal models are routinely used to investigate such events in the lung, but they do not truly reproduce the responses that occur in humans. Scientists committed to the more robust Three Rs principles of animal experimentation (Reduction, Refinement and Replacement) have been developing viable alternatives, derived from human medical waste tissues from patient donors, to generate in vitro models that resemble the in vivo human lung environment. In the specific case of inhalation toxicology, human-oriented models are especially warranted, given the new REACH regulations for the handling of chemicals, the rising air pollution problems and the availability of pharmaceutically valuable drugs. Advances in tissue-engineering have made it feasible and cost-effective to construct human tissue equivalents of the respiratory epithelia. The conducting airways of the lower respiratory system are a critical zone to recapitulate for use in inhalation toxicology. Three-dimensional (3-D) tissue designs which make use of primary cells, provide more in vivo-like responses, based on the targeted interactions of multiple cell types supported on artificial scaffolds. These scaffolds emulate the native extracellular matrix, in which cells differentiate into a functional pulmonary tissue. When 3-D cell cultures are employed for testing aerosolised chemicals, drugs and xenobiotics, responses are captured that mirror the events in the in situ human lung and provide human endpoint data.
呼吸系统是空气传播物质进入人体的门户，这些物质可能通过给药途径或在不经意间吸入环境空气（例如空气污染）进入人体。肺部疾病的负担一直在持续增加，以至于现在它是全球范围内人类发病率和死亡率的主要原因。在英国，死于呼吸疾病的人数超过死于冠心病或非呼吸性癌症的人数。仅出于这一原因，了解人类肺部生物学的机制，尤其是在损伤和修复事件中，现在是呼吸医学领域的主要焦点。动物模型通常用于研究肺部的此类事件，但它们并不能真正复制人类发生的反应。致力于动物实验更严格的三 R 原则（减少、优化和替代）的科学家一直在开发可行的替代品，这些替代品源自患者供体的人类医疗废物组织，以生成类似于体内人类肺部环境的体外模型。在吸入毒理学的特定情况下，鉴于新的 REACH 法规处理化学品、日益严重的空气污染问题和具有药用价值的药物的可用性，特别需要面向人类的模型。组织工程学的进步使得构建呼吸系统上皮的人类组织等效物成为可行且具有成本效益的方法。下呼吸道的传导气道是一个需要重现的关键区域，用于吸入毒理学研究。使用原代细胞的三维（3-D）组织设计提供了更类似于体内的反应，这是基于在人工支架上支持的多种细胞类型的靶向相互作用。这些支架模拟了细胞分化为功能性肺组织的固有细胞外基质。当 3-D 细胞培养物用于测试气溶胶化化学品、药物和外源性物质时，会捕获到反映原位人肺中发生的事件并提供人终点数据的反应。
