Amano Hiroyuki, Murata Kazuya, Matsunaga Hirofumi, Tanaka Kensuke, Yoshioka Kento, Kobayashi Takeshi, Ishida Junji, Fukamizu Akiyoshi, Sugiyama Fumihiro, Sudo Tatsuhiko, Kimura Sadao, Tatsumi Koichiro, Kasuya Yoshitoshi
Department of Biochemistry and Molecular Pharmacology .
J Recept Signal Transduct Res. 2014 Aug;34(4):299-306. doi: 10.3109/10799893.2014.896380. Epub 2014 Mar 5.
There are few short-term mouse models of chronic obstructive pulmonary disease (COPD) mimicking the human disease. In addition, p38 is recently recognized as a target for the treatment of COPD. However, the precise mechanism how p38 contributes to the pathogenesis of COPD is still unknown.
We attempted to create a new mouse model for COPD by intra-tracheal administration of a mixture of lipopolysaccharide (LPS) and cigarette smoke solution (CSS), and investigated the importance of the p38 mitogen-activated protein kinase (p38) pathway in the pathogenesis of COPD.
Mice were administered LPS + CSS once a day on days 0-4 and 7-11. Thereafter, CSS alone was administered to mice once a day on days 14-18. On day 28, histopathological changes of the lung were evaluated, and bronchoalveolar lavage fluid (BALF) was subjected to western blot array for cytokines. Transgenic (TG) mice expressing a constitutive-active form of MKK6, a p38-specific activator in the lung, were subjected to our experimental protocol of COPD model.
LPS + CSS administration induced enlargement of alveolar air spaces and destruction of lung parenchyma. BALF analyses of the LPS + CSS group revealed an increase in expression levels of several cytokines involved in the pathogenesis of human COPD. These results suggest that our experimental protocol can induce COPD in mice. Likewise, histopathological findings of the lung and induction of cytokines in BALF from MKK6 c.a.-TG mice were more marked than those in WT mice.
In a new experimental COPD mouse model, p38 accelerates the development of emphysema.
几乎没有能模拟人类疾病的慢性阻塞性肺疾病（COPD）短期小鼠模型。此外，p38最近被认为是COPD治疗的一个靶点。然而，p38如何促成COPD发病机制的确切机制仍不清楚。
我们试图通过气管内给予脂多糖（LPS）和香烟烟雾溶液（CSS）的混合物来创建一种新的COPD小鼠模型，并研究p38丝裂原活化蛋白激酶（p38）途径在COPD发病机制中的重要性。
在第0 - 4天和第7 - 11天，每天给小鼠一次LPS + CSS。此后，在第14 - 18天每天给小鼠一次单独的CSS。在第28天，评估肺的组织病理学变化，并对支气管肺泡灌洗液（BALF）进行细胞因子的蛋白质印迹阵列分析。对表达肺中p38特异性激活剂MKK6组成型活性形式的转基因（TG）小鼠实施我们的COPD模型实验方案。
给予LPS + CSS导致肺泡气腔扩大和肺实质破坏。LPS + CSS组的BALF分析显示，参与人类COPD发病机制的几种细胞因子的表达水平增加。这些结果表明我们的实验方案可在小鼠中诱导出COPD。同样，MKK6组成型活性TG小鼠肺的组织病理学发现和BALF中细胞因子的诱导比野生型小鼠更明显。
在一种新的实验性COPD小鼠模型中，p38加速肺气肿的发展。
