Brusselle G G, Bracke K R, Maes T, D'hulst A I, Moerloose K B, Joos G F, Pauwels R A
Department of Respiratory Diseases, Ghent University Hospital and Ghent University, Belgium.
Pulm Pharmacol Ther. 2006;19(3):155-65. doi: 10.1016/j.pupt.2005.06.001. Epub 2005 Aug 3.
Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, that is not fully reversible, and that is associated with an abnormal inflammatory response of the airways and lungs to noxious particles and gases. The airflow limitation is caused by increased resistance of the small conducting airways and by decreased elastic recoil forces of the lung due to emphysematous destruction of the lung parenchyma. In vivo animal models can help to unravel the molecular and cellular mechanisms underlying the pathogenesis of COPD. Mice represent the most favored animal species with regard to the study of (both innate and adaptive) immune mechanisms, since they offer the opportunity to manipulate gene expression. Several experimental approaches are applied in order to mimic the different traits of COPD in these murine models. Firstly, the tracheal instillation of tissue-degrading enzymes induces emphysema-like lesions in the lung parenchyma, adding further proof to the protease-antiprotease imbalance hypothesis. Secondly, the inhalation of noxious stimuli, including tobacco smoke, sulfur dioxide, nitrogen dioxide, or oxidants such as ozone, may also lead to COPD-like lesions in mice, depending on concentration, duration of exposure and strainspecific genetic susceptibility. Thirdly, in transgenic mice, a specific gene is either overexpressed (non-specific or organ-specific) or selectively depleted (constitutively or conditionally). The study of these transgenic mice, either per se or in combination with the above mentioned experimental approaches (e.g. the inhalation of tobacco smoke), can offer valuable information on both the physiological function of the gene of interest as well as the pathophysiological mechanisms of diseases with complex traits such as COPD.
慢性阻塞性肺疾病（COPD）的特征是气流受限，这种受限不完全可逆，且与气道和肺部对有害颗粒及气体的异常炎症反应相关。气流受限是由小传导气道阻力增加以及由于肺实质的肺气肿性破坏导致肺弹性回缩力降低所致。体内动物模型有助于揭示COPD发病机制背后的分子和细胞机制。就（先天和适应性）免疫机制的研究而言，小鼠是最受青睐的动物物种，因为它们提供了操纵基因表达的机会。为了在这些小鼠模型中模拟COPD的不同特征，应用了几种实验方法。首先，气管内滴注组织降解酶可在肺实质中诱导出类似肺气肿的病变，为蛋白酶 - 抗蛋白酶失衡假说提供了进一步证据。其次，吸入有害刺激物，包括烟草烟雾、二氧化硫、二氧化氮或氧化剂如臭氧，根据浓度、暴露持续时间和品系特异性遗传易感性，也可能导致小鼠出现类似COPD的病变。第三，在转基因小鼠中，特定基因要么过度表达（非特异性或器官特异性），要么被选择性去除（组成性或条件性）。对这些转基因小鼠本身或与上述实验方法（如吸入烟草烟雾）结合进行研究，可以提供有关感兴趣基因的生理功能以及诸如COPD等具有复杂特征疾病的病理生理机制的有价值信息。
