GRP78 and CHOP modulate macrophage apoptosis and the development of bleomycin-induced pulmonary fibrosis
GRP78 and CHOP modulate macrophage apoptosis and the development of bleomycin-induced pulmonary fibrosis
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DOI：
10.1002/path.4738
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发表时间：
2016-08-01
影响因子：
7.3
通讯作者：
Ask, Kjetil
中科院分区：
文献类型：
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作者：
Ayaub, Ehab A.;Kolb, Philipp S.;Ask, Kjetil
内质网（ER）应激和未折叠蛋白反应（UPR）与纤维化肺疾病有关，尽管它们究竟如何调节这一过程仍不清楚。在这里，我们研究了主要UPR调节剂GRP 78在肺损伤和纤维化实验模型中的作用。通过口咽插管将Grp 78（+/-）、Chop（-/-）和野生型C57 BL 6/J小鼠暴露于博来霉素，并在第7天和第21天检查肺。我们在这里证明，Grp 78（+/-）小鼠受到强烈保护，免受博来霉素诱导的纤维化，如免疫组织化学分析、胶原蛋白含量和肺功能测量所示。在该模型的炎症阶段，在Grp 78（+/-）小鼠中观察到肺巨噬细胞数量减少，与TUNEL阳性细胞数量增加相关。双重免疫组织化学和原位杂交实验表明，从受保护的Grp 78（+/-）小鼠的巨噬细胞群体也强阳性切割的caspase-3和Chop mRNA，分别。相比之下，博来霉素对Chop（-/-）小鼠的给药导致准静态弹性和细胞外基质沉积增加，这与实质性胱天蛋白酶-1阳性巨噬细胞数量增加有关，而这些巨噬细胞对裂解的胱天蛋白酶-3呈阴性。提供的数据表明，UPR在纤维化肺组织中被激活，并强烈定位于巨噬细胞。GRP 78和CHOP介导的巨噬细胞凋亡被发现可以防止博莱霉素诱导的纤维化。总的来说，我们在这里证明，博莱霉素的纤维化反应是依赖于GRP 78介导的事件，并提供证据表明，巨噬细胞极化和细胞凋亡可能在这个过程中发挥作用。版权所有（C）2016大不列颠及爱尔兰病理学会。由John Wiley & Sons有限公司出版
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been associated with fibrotic lung disease, although exactly how they modulate this process remains unclear. Here we investigated the role of GRP78, the main UPR regulator, in an experimental model of lung injury and fibrosis. Grp78(+/-), Chop(-/-) and wild type C57BL6/J mice were exposed to bleomycin by oropharyngeal intubation and lungs were examined at days 7 and 21. We demonstrate here that Grp78(+/-) mice were strongly protected from bleomycin-induced fibrosis, as shown by immunohistochemical analysis, collagen content and lung function measurements. In the inflammatory phase of this model, a reduced number of lung macrophages associated with an increased number of TUNEL-positive cells were observed in Grp78(+/-) mice. Dual immunohistochemical and in situ hybridization experiments showed that the macrophage population from the protected Grp78(+/-) mice was also strongly positive for cleaved caspase-3 and Chop mRNA, respectively. In contrast, the administration of bleomycin to Chop(-/-) mice resulted in increased quasi-static elastance and extracellular matrix deposition associated with an increased number of parenchymal arginase-1-positive macrophages that were negative for cleaved caspase-3. The data presented indicate that the UPR is activated in fibrotic lung tissue and strongly localized to macrophages. GRP78-and CHOP-mediated macrophage apoptosis was found to protect against bleomycin-induced fibrosis. Overall, we demonstrate here that the fibrotic response to bleomycin is dependent on GRP78-mediated events and provides evidence that macrophage polarization and apoptosis may play a role in this process. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.