The Thoracic Diseases Research Unit, Division of Pulmonary Critical Care, Department of Internal Medicine, the Clinical Immunology and Immunotherapeutics Program, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA.
Respir Res. 2010 Apr 26;11(1):45. doi: 10.1186/1465-9921-11-45.
Abnormal immune responses are believed to be highly relevant in the pathogenesis of chronic obstructive pulmonary disease (COPD). Dendritic cells provide a critical checkpoint for immunity by their capacity to both induce and suppress immunity. Although evident that cigarette smoke, the primary cause of COPD, significantly influences dendritic cell functions, little is known about the roles of dendritic cells in the pathogenesis of COPD.
The extent of dendritic cell infiltration in COPD tissue specimens was determined using immunohistochemical localization of CD83+ cells (marker of matured myeloid dendritic cells), and CD1a+ cells (Langerhans cells). The extent of tissue infiltration with Langerhans cells was also determined by the relative expression of the CD207 gene in COPD versus control tissues. To determine mechanisms by which dendritic cells accumulate in COPD, complimentary studies were conducted using monocyte-derived human dendritic cells exposed to cigarette smoke extract (CSE), and dendritic cells extracted from mice chronically exposed to cigarette smoke.
In human COPD lung tissue, we detected a significant increase in the total number of CD83+ cells, and significantly higher amounts of CD207 mRNA when compared with control tissue. Human monocyte-derived dendritic cells exposed to CSE (0.1-2%) exhibited enhanced survival in vitro when compared with control dendritic cells. Murine dendritic cells extracted from mice exposed to cigarette smoke for 4 weeks, also demonstrated enhanced survival compared to dendritic cells extracted from control mice. Acute exposure of human dendritic cells to CSE induced the cellular pro-survival proteins heme-oxygenase-1 (HO-1), and B cell lymphoma leukemia-x(L) (Bcl-xL), predominantly through oxidative stress. Although activated human dendritic cells conditioned with CSE expressed diminished migratory CCR7 expression, their migration towards the CCR7 ligand CCL21 was not impaired.
These data indicate that COPD is associated with increased numbers of cells bearing markers associated with Langerhans cells and mature dendritic cells, and that cigarette smoke promotes survival signals and augments survival of dendritic cells. Although CSE suppressed dendritic cell CCR7 expression, migration towards a CCR7 ligand was not diminished, suggesting that reduced CCR7-dependent migration is unlikely to be an important mechanism for dendritic cell retention in the lungs of smokers with COPD.
异常的免疫反应被认为与慢性阻塞性肺疾病（COPD）的发病机制密切相关。树突状细胞通过诱导和抑制免疫的能力，为免疫提供了一个关键的检查点。虽然香烟烟雾是 COPD 的主要病因，它明显影响树突状细胞的功能，但人们对树突状细胞在 COPD 发病机制中的作用知之甚少。
通过 CD83+细胞（成熟髓样树突状细胞的标志物）和 CD1a+细胞（朗格汉斯细胞）的免疫组织化学定位，确定 COPD 组织标本中树突状细胞的浸润程度。通过 COPD 与对照组织中 CD207 基因的相对表达，也确定了朗格汉斯细胞在组织浸润中的程度。为了确定树突状细胞在 COPD 中积累的机制，我们还进行了补充研究，使用暴露于香烟烟雾提取物（CSE）的单核细胞来源的人树突状细胞和慢性暴露于香烟烟雾的小鼠中提取的树突状细胞。
在人类 COPD 肺组织中，我们检测到 CD83+细胞的总数显著增加，与对照组织相比，CD207 mRNA 的含量也显著增加。与对照树突状细胞相比，暴露于 0.1-2% CSE 的人单核细胞来源的树突状细胞在体外的存活率更高。从暴露于香烟烟雾 4 周的小鼠中提取的树突状细胞，与从对照小鼠中提取的树突状细胞相比，存活率也更高。急性暴露于 CSE 的人树突状细胞诱导细胞存活蛋白血红素加氧酶-1（HO-1）和 B 细胞淋巴瘤白血病-x（Bcl-xL）的表达，主要通过氧化应激。尽管用 CSE 处理的激活人树突状细胞表达的趋化因子受体 7（CCR7）表达减少，但它们向 CCR7 配体 CCL21 的迁移不受影响。
这些数据表明，COPD 与携带与朗格汉斯细胞和成熟树突状细胞相关标志物的细胞数量增加有关，香烟烟雾促进了树突状细胞存活信号的产生，并增强了树突状细胞的存活。尽管 CSE 抑制了树突状细胞的 CCR7 表达，但向 CCR7 配体的迁移并未减少，这表明减少 CCR7 依赖性迁移不太可能是吸烟者 COPD 肺部树突状细胞保留的重要机制。
Zotero 插件
