Increased Pulmonary GM-CSF Causes Alveolar Macrophage Accumulation. Mechanistic Implications for Desquamative Interstitial Pneumonitis.
Increased Pulmonary GM-CSF Causes Alveolar Macrophage Accumulation. Mechanistic Implications for Desquamative Interstitial Pneumonitis.
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肺 GM-CSF 增加导致肺泡巨噬细胞积聚。
DOI：
10.1165/rcmb.2018-0294oc
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发表时间：
2020
影响因子：
6.4
通讯作者：
Trapnell,BruceC
中科院分区：
文献类型：
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作者：
Suzuki,Takuji;McCarthy,Cormac;Carey,BrennaC;Borchers,Michael;Beck,David;Wikenheiser-Brokamp,KathrynA;Black,Dianna;Chalk,Claudia;Trapnell,BruceC
脱屑性间质性肺炎（DIP）是一种罕见的、与吸烟相关的弥漫性肺实质疾病，其特征是肺泡巨噬细胞（AM）显著积聚和肺气肿，无广泛纤维化或嗜酸性炎症。由于吸烟增加了肺GM-CSF（粒细胞/巨噬细胞集落刺激因子）的表达，GM-CSF刺激AM的增殖和活化，我们假设小鼠长期暴露于增加的肺GM-CSF可能重演DIP。野生型（WT）小鼠吸入香烟烟雾暴露16个月，AM数量和肺GM-CSF mRNA水平进行了测量。在证实烟雾吸入可增加WT小鼠的肺GM-CSF后，使用过表达肺GM-CSF的转基因小鼠（SPC-GM-CSF+/+）来确定长期暴露于增加的肺GM-CSF（无烟雾吸入）对AM蓄积和活化、肺基质金属蛋白酶（MMP）表达和活性、肺组织病理学、红细胞增多症发展和存活的影响。在WT小鼠中，烟雾暴露显著增加肺GM-CSF和AM积累。在未暴露的SPC-GM-CSF+/+小鼠中，如STAT 5（信号诱导剂和转录激活因子5）磷酸化所示，AM自发活化，并在10月龄时进行性蓄积，累及84%（四分位数间距，55-90%）的肺实质。组织学特征还包括散在的多核巨细胞、肺泡上皮细胞增生和轻度肺泡壁增厚。与WT小鼠相比，SPC-GM-CSF+/+小鼠的肺MMP-9和MMP-12水平升高，自发发生肺气肿和继发性红细胞增多症，死亡率升高。结果表明，香烟烟雾增加肺GM-CSF和AM增殖，并且肺GM-CSF的慢性增加概括了DIP的主要特征，包括AM积聚、肺气肿、继发性红细胞增多症和小鼠死亡率增加。这些观察结果表明，肺GM-CSF可能参与DIP的发病机制。
Desquamative interstitial pneumonia (DIP) is a rare, smoking-related, diffuse parenchymal lung disease characterized by marked accumulation of alveolar macrophages (AMs) and emphysema, without extensive fibrosis or neutrophilic inflammation. Because smoking increases expression of pulmonary GM-CSF (granulocyte/macrophage–colony stimulating factor) and GM-CSF stimulates proliferation and activation of AMs, we hypothesized that chronic exposure of mice to increased pulmonary GM-CSF may recapitulate DIP. Wild-type (WT) mice were subjected to inhaled cigarette smoke exposure for 16 months, and AM numbers and pulmonary GM-CSF mRNA levels were measured. After demonstrating that smoke inhalation increased pulmonary GM-CSF in WT mice, transgenic mice overexpressing pulmonary GM-CSF (SPC-GM-CSF+/+) were used to determine the effects of chronic exposure to increased pulmonary GM-CSF (without smoke inhalation) on accumulation and activation of AMs, pulmonary matrix metalloproteinase (MMP) expression and activity, lung histopathology, development of polycythemia, and survival. In WT mice, smoke exposure markedly increased pulmonary GM-CSF and AM accumulation. In unexposed SPC-GM-CSF+/+mice, AMs were spontaneously activated as shown by phosphorylation of STAT5 (signal inducer and activator of transcription 5) and accumulated progressively with involvement of 84% (interquartile range, 55–90%) of the lung parenchyma by 10 months of age. Histopathologic features also included scattered multinucleated giant cells, alveolar epithelial cell hyperplasia, and mild alveolar wall thickening. SPC-GM-CSF+/+mice had increased pulmonary MMP-9 and MMP-12 levels, spontaneously developed emphysema and secondary polycythemia, and had increased mortality compared with WT mice. Results show cigarette smoke increased pulmonary GM-CSF and AM proliferation, and chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP, including AM accumulation, emphysema, secondary polycythemia, and increased mortality in mice. These observations suggest pulmonary GM-CSF may be involved in the pathogenesis of DIP.