Aida Yasuko, Shibata Yoko, Abe Shuichi, Inoue Sumito, Kimura Tomomi, Igarashi Akira, Yamauchi Keiko, Nunomiya Keiko, Kishi Hiroyuki, Nemoto Takako, Sato Masamichi, Sato-Nishiwaki Michiko, Nakano Hiroshi, Sato Kento, Kubota Isao
Department of Cardiology, Pulmonology, and Nephrology, School of Medicine, Yamagata University, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Int J Biol Sci. 2014 Aug 13;10(8):882-94. doi: 10.7150/ijbs.8737. eCollection 2014.
Alveolar macrophages (AMs) play important roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously demonstrated upregulation of the transcription factor MafB in AMs of mice exposed to cigarette smoke. The aim of this study was to elucidate the roles of MafB in the development of pulmonary emphysema. Porcine pancreatic elastase was administered to wild-type (WT) and dominant-negative (DN)-MafB transgenic (Tg) mice in which MafB activity was suppressed only in macrophages. We measured the mean linear intercept and conducted cell differential analysis of bronchoalveolar lavage (BAL) cells, surface marker analysis using flow cytometry, and immunohistochemical staining using antibodies to matrix metalloproteinase (MMP)-9 and MMP-12. Airspace enlargement of the lungs was suppressed significantly in elastase-treated DN-MafB Tg mice compared with treated WT mice. AMs with projected pseudopods were decreased in DN-MafB Tg mice. The number of cells intermediately positive for F4/80 and weakly or intermediately positive for CD11b, which are considered cell subsets of matured AMs, decreased in the BAL of DN-MafB Tg mice. Furthermore, MMP-9 and -12 were significantly downregulated in BAL cells of DN-MafB Tg mice. Because MMPs exacerbate emphysema, MafB may be involved in pulmonary emphysema development through altered maturation of macrophages and MMP expression.
肺泡巨噬细胞（AMs）在慢性阻塞性肺疾病（COPD）的发病机制中起重要作用。我们之前证明了暴露于香烟烟雾的小鼠AMs中转录因子MafB上调。本研究的目的是阐明MafB在肺气肿发展中的作用。将猪胰弹性蛋白酶给予野生型（WT）和显性负性（DN）-MafB转基因（Tg）小鼠，其中MafB活性仅在巨噬细胞中受到抑制。我们测量了平均线性截距，并对支气管肺泡灌洗（BAL）细胞进行了细胞差异分析，使用流式细胞术进行表面标志物分析，以及使用基质金属蛋白酶（MMP）-9和MMP-12抗体进行免疫组织化学染色。与经处理的WT小鼠相比，经弹性蛋白酶处理的DN-MafB Tg小鼠肺部的气腔扩大得到显著抑制。DN-MafB Tg小鼠中具有突出伪足的AMs减少。在DN-MafB Tg小鼠的BAL中，F4/80呈中等阳性且CD11b呈弱阳性或中等阳性的细胞数量减少，这些细胞被认为是成熟AMs的细胞亚群。此外，DN-MafB Tg小鼠BAL细胞中的MMP-9和-12显著下调。由于MMP会加重肺气肿，MafB可能通过改变巨噬细胞成熟和MMP表达而参与肺气肿的发展。
