Interstitial pneumonia induced by bleomycin treatment is exacerbated in Angptl2-deficient mice
Interstitial pneumonia induced by bleomycin treatment is exacerbated in Angptl2-deficient mice
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DOI：
10.1152/ajplung.00005.2016
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发表时间：
2016-10-01
影响因子：
4.9
通讯作者：
Oike, Yuichi
中科院分区：
文献类型：
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作者：
Motokawa, Ikuyo;Endo, Motoyoshi;Oike, Yuichi
血管生成素样蛋白2（ANGPTL2）是一种慢性炎症介质，当其失调时，与各种病理学相关。然而，关于其在肺中的活性知之甚少。为了评估可能的肺功能，我们产生了特异性识别小鼠ANGPTL2的兔单克隆抗体，然后评估了小鼠肺组织中的蛋白质表达。在正常条件下，我们观察到肺泡上皮I型和II型细胞以及驻留肺泡巨噬细胞中有丰富的ANGPTL2表达。为了评估ANGPTL2功能，我们比较了Angptl2敲除（KO）和野生型小鼠的肺表型，但没有观察到明显的变化。然后，我们使用野生型和Angptl2 KO小鼠产生博来霉素诱导的间质性肺炎模型。博来霉素处理的野生型小鼠在严重纤维化间质性肺炎区域中显示出特异性上调的ANGPTL2表达，而Angptl2 KO小鼠比博来霉素处理的野生型小鼠发展出更严重的肺纤维化。骨髓移植后观察到的肺纤维化在用博来霉素处理的野生型或Angptl2 KO小鼠中相当，表明骨髓细胞中的Angptl2损失不构成纤维化表型的基础。我们得出结论，肺上皮细胞和驻留的肺泡巨噬细胞中的Angptl2缺乏导致博来霉素治疗后观察到的严重肺纤维化，表明源自这些细胞类型的ANGPTL2对肺纤维化起保护作用。
Angiopoietin-like protein 2 (ANGPTL2) is a chronic inflammatory mediator that, when deregulated, is associated with various pathologies. However, little is known about its activity in lung. To assess a possible lung function, we generated a rabbit monoclonal antibody that specifically recognizes mouse ANGPTL2 and then evaluated protein expression in mouse lung tissue. We observed abundant ANGPTL2 expression in both alveolar epithelial type I and type II cells and in resident alveolar macrophages under normal conditions. To assess ANGPTL2 function, we compared lung phenotypes in Angptl2 knockout (KO) and wild-type mice but observed no overt changes. We then generated a bleomycin-induced interstitial pneumonia model using wild-type and Angptl2 KO mice. Bleomycin-treated wild-type mice showed specifically upregulated ANGPTL2 expression in areas of severe fibrosing interstitial pneumonia, while Angptl2 KO mice developed more severe lung fibrosis than did comparably treated wild-type mice. Lung fibrosis seen following bone marrow transplant was comparable in wild-type or Angptl2 KO mice treated with bleomycin, suggesting that Angptl2 loss in myeloid cells does not underlie fibrotic phenotypes. We conclude that Angptl2 deficiency in lung epithelial cells and resident alveolar macrophages causes severe lung fibrosis seen following bleomycin treatment, suggesting that ANGPTL2 derived from these cell types plays a protective role against fibrosis in lung.