Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II cells
Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II cells
复制标题
DOI：
10.4049/jimmunol.178.8.5001
复制
发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Tanaka, Masato
中科院分区：
文献类型：
--
作者：
Miyake, Yasunobu;Kaise, Hitomi;Tanaka, Masato
巨噬细胞具有多种活性，并且巨噬细胞的不同表型如何在体内不同类型的组织损伤中促成病理状况在很大程度上是未知的。本研究通过建立肺泡Ⅱ型上皮细胞（AE 2）功能障碍所致的急性呼吸窘迫综合征动物模型，探讨肺泡巨噬细胞在急性肺损伤中的作用。人白喉毒素（DT）受体（DTR），肝素结合表皮生长因子样生长因子（HB-EGF），在溶菌酶M（LysM）基因启动子的控制下，在小鼠中表达。DT给药后，小鼠出现急性肺损伤，并在4天内死亡。免疫组化结果显示DT组小鼠肺泡巨噬细胞和AE 2细胞均通过凋亡而消失。与AE 2细胞的缺失一致，DT处理的转基因小鼠支气管肺泡灌洗液中表面活性蛋白的量大大减少。当将野生型小鼠的骨髓移植到照射过的LysM-DTR小鼠中时，肺泡巨噬细胞变得对DT具有抗性，但小鼠仍然遭受DT给药引起的急性肺损伤。与DT给药后AE 2细胞和巨噬细胞均被清除的小鼠相比，DT治疗后巨噬细胞耐药的LysM-DTR小鼠的肺损伤程度较轻，支气管肺泡灌洗液中肝细胞生长因子的含量减少。这些结果表明，巨噬细胞在AE 2细胞选择性消融引起的非炎性肺损伤中起保护作用。
Macrophages have a wide variety of activities and it is largely unknown how the diverse phenotypes of macrophages contribute to pathological conditions in the different types of tissue injury in vivo. In this study we established a novel animal model of acute respiratory distress syndrome caused by the dysfunction of alveolar epithelial type II (AE2) cells and examined the roles of alveolar macrophages in the acute lung injury. The human diphtheria toxin (DT) receptor (DTR), heparin-binding epidermal growth factor-like growth factor (HB-EGF), was expressed under the control of the lysozyme M (LysM) gene promoter in the mice. When DT was administrated to the mice they suffered from acute lung injury and died within 4 days. Immunohistochemical examination revealed that AE2 cells as well as alveolar macrophages were deleted via apoptosis in the mice treated with DT. Consistent with the deletion of AE2 cells, the amount of surfactant proteins in bronchoalveolar lavage fluid was greatly reduced in the DT-treated transgenic mice. When bone marrow from wild-type mice was transplanted into irradiated LysM-DTR mice, the alveolar macrophages became resistant to DT but the mice still suffered from acute lung injury by DT administration. Compared with the mice in which both AE2 cells and macrophages were deleted by DT administration, the DT-treated LysM-DTR mice with DT-resistant macrophages showed less severe lung injury with a reduced amount of hepatocyte growth factor in bronchoalveolar lavage fluid. These results indicate that macrophages play a protective role in noninflammatory lung injury caused by the selective ablation of AE2 cells.