Project 3: Mouse Models of Smoking-related Diseases: What is the Best

烟草烟雾对健康有毁灭性的影响，特别是对肺部健康。这是最常见的原因 慢性阻塞性肺病(COPD)和肺癌。它也对许多其他的 肺部疾病，包括间质性肺病和肺炎。大多数烟草相关的小鼠模型 肺病使小鼠品系暴露在烟草烟雾中。此模型通常会导致轻度到中度 肺气肿，但很少或根本没有慢性支气管炎的证据，慢性支气管炎是人类慢性阻塞性肺疾病的主要组成部分。 我们的目标是建立一种烟草烟雾诱导的肺损伤模型，该模型模仿在人类中发现的模型。这 这项工作将解决FDA CPT研究兴趣--“不良健康后果”。这个项目的目标是 确定哪些动物模型可以被验证以建立标准的毒性变化以及什么 活体检测中观察到的大小与人类健康结果的变化相关(第31点)。 如项目1所述，烟雾暴露会导致CFTR活性降低，从而导致对 呼吸道液体积水，粘液脱水，粘液纤毛清除不良。转基因小鼠 过度表达Scnnib，编码上皮性Na*Chanriel亚单位(PENaC)的基因，在 呼吸道上皮细胞模仿烟草烟雾的这一方面，表现为粘液细胞化生，粘液 高分泌和梗阻，中性粒细胞炎症，巨大的泡沫巨噬细胞，并增加 管腔和管壁均可见淋巴细胞数量。这些老鼠也有证据表明 一种依赖于基质金属蛋白酶-12的肺气肿成分与损伤有关。因此，这些小鼠的肺部发育 模拟COPD患者发现的变化的病理学，突出了呼吸道的显著影响 脱水。然而，这些老鼠忽略了烟草烟雾的所有其他影响，这些影响很可能是 许多是由于烟草烟雾中的许多成分造成的。我们正在建立烟草烟雾暴露的模型 将Scnn1b-Tg小鼠暴露在长期(6个月)的烟草烟雾暴露中。我们迄今为止的研究 这表明，到目前为止，这个模型比老鼠模型更接近于人类的伤害。尤其是，基因 表达分析表明，scnnlb-ig小鼠的烟雾暴露导致更多与人类相似的结果 解毒途径和免疫调节途径中的疾病。到目前为止，其他相似之处包括 呼吸道内粘蛋白的变化和大量囊泡外体的存在。因此，我们 建议检验Scnn1b-TG小鼠烟雾暴露是人类优秀模型的假设 与野生型(WT)小鼠或其他COPD小鼠模型相比，可以更有效地利用该疾病 研究烟雾的特定成分，或比较烟草产品或替代品。

Tobacco smoke has a devastating impact on health, particularly on lung health. It is the most common cause of chronic obstructive lung disease (COPD) and lung cancer. It also has synergistic effects on numerous other lung diseases, including interstitial lung disease and pneumonia. Most mouse models oftobacco smokerelated lung disease expose mouse strains to tobacco smoke. This model usually results in mild-to-moderate emphysema, but little or no evidence ofthe chronic bronchitis, which is a large component of COPD in humans. Our aim is to establish a model oftobacco smoke-induced lung injury that mimics that found in humans. This work will address the FDA CPT research interest, "Adverse Health Consequences". The goal ofthis project is to determine what animal models can be validated to establish standard toxicity changes and what magnitude observed within in vivo assays correlates with change in human health outcome (point 31). As described in Project 1, smoke exposure leads to decreased activity of CFTR, resulting in absorption of water from airway liquid, dehydration of mucus, and poor mucociliary clearance. Transgenic mice overexpressing Scnnib, the gene which codes forthe epithelial Na* chanriel subunit (pENaC), in the epithelial cells ofthe airways mimic this aspect oftobacco smoke, showing mucus cell metaplasia, mucus hypersecretion and obstruction, neutrophilic inflammation, large foamy macrophages, and increased numbers of lymphocytes in both the lumen and the walls ofthe ainways. These mice also show evidence of an MMP-12-dependent emphysematous component to the injury. Thus, the lungs of these mice develop pathology that mimics changes found in COPD patients, highlighting the striking effects of airway dehydration. However, these mice are missing all other effects oftobacco smoke, which are likely to be many due to numerous components of tobacco smoke. We are modeling tobacco smoke exposure in humans by exposing Scnn1b-tg mice to prolonged (6 month) tobacco smoke exposure. Our studies to date suggest that this model mimics the human injury more closely than mouse models to date. In particular, gene expression analysis suggests that smoke exposure in Scnnlb-ig mice results in more similarities to human disease in both detoxification pathways and in immune regulatory pathways. Other similarities to date include changes in mucins within the airways and the presence of large numbers of vesicular exosomes. Thus, we propose to test the hypothesis that smoke exposure in Scnn1b-tg mice is an excellent model of human disease and can be used more effectively than either wild type (WT) mice or other mouse models of COPD to study particular components of smoke or to compare tobacco products or substitutes.