Habiel David M, Camelo Ana, Espindola Milena, Burwell Timothy, Hanna Richard, Miranda Elena, Carruthers Alan, Bell Matthew, Coelho Ana Lucia, Liu Hao, Pilataxi Fernanda, Clarke Lori, Grant Ethan, Lewis Arthur, Moore Bethany, Knight Darryl A, Hogaboam Cory M, Murray Lynne A
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Cambridge, United Kingdom.
Sci Rep. 2017 Nov 13;7(1):15444. doi: 10.1038/s41598-017-15670-5.
Lung fibrosis is an unabated wound healing response characterized by the loss and aberrant function of lung epithelial cells. Herein, we report that extracellular Clusterin promoted epithelial cell apoptosis whereas intracellular Clusterin maintained epithelium viability during lung repair. Unlike normal and COPD lungs, IPF lungs were characterized by significantly increased extracellular Clusterin whereas the inverse was evident for intracellular Clusterin. In vitro and in vivo studies demonstrated that extracellular Clusterin promoted epithelial cell apoptosis while intercellular Clusterin modulated the expression of the DNA repair proteins, MSH2, MSH6, OGG1 and BRCA1. The fibrotic response in Clusterin deficient (CLU-/-) mice persisted after bleomycin and it was associated with increased DNA damage, reduced DNA repair responses, and elevated cellular senescence. Remarkably, this pattern mirrored that observed in IPF lung tissues. Together, our results show that cellular localization of Clusterin leads to divergent effects on epithelial cell regeneration and lung repair during fibrosis.
肺纤维化是一种持续存在的伤口愈合反应，其特征在于肺上皮细胞的丧失和功能异常。在此，我们报告细胞外聚集素促进上皮细胞凋亡，而细胞内聚集素在肺修复过程中维持上皮细胞的活力。与正常肺和慢性阻塞性肺疾病（COPD）的肺不同，特发性肺纤维化（IPF）的肺的特征是细胞外聚集素显著增加，而细胞内聚集素则相反。体外和体内研究表明，细胞外聚集素促进上皮细胞凋亡，而细胞间聚集素调节DNA修复蛋白MSH2、MSH6、OGG1和BRCA1的表达。博来霉素处理后，聚集素缺陷（CLU-/-）小鼠的纤维化反应持续存在，并且与DNA损伤增加、DNA修复反应减少和细胞衰老升高有关。值得注意的是，这种模式与IPF肺组织中观察到的模式相似。总之，我们的结果表明，聚集素的细胞定位在纤维化过程中对上皮细胞再生和肺修复产生不同的影响。
